EP1140067A1 - Antiviral method using mek inhibitors - Google Patents

Antiviral method using mek inhibitors

Info

Publication number
EP1140067A1
EP1140067A1 EP99966522A EP99966522A EP1140067A1 EP 1140067 A1 EP1140067 A1 EP 1140067A1 EP 99966522 A EP99966522 A EP 99966522A EP 99966522 A EP99966522 A EP 99966522A EP 1140067 A1 EP1140067 A1 EP 1140067A1
Authority
EP
European Patent Office
Prior art keywords
methyl
phenylamino
iodo
benzamide
difluoro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99966522A
Other languages
German (de)
French (fr)
Inventor
Alexander James Bridges
David Thomas Dudley
Stephen Joseph Gracheck
Annette Lynn Meyer
Alan Robert Saltiel
Judith Sebolt-Leopold
Peter Craig Weber
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Co LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of EP1140067A1 publication Critical patent/EP1140067A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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

Definitions

  • 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
  • ERK extracellular signal-regulated kinase
  • 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.
  • 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.
  • 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.
  • Warts 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.
  • 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.
  • 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.
  • the invention provides a method for preventing or treating viral infections in mammals by administering a selective
  • MEK inhibitor is those compounds which inhibit the MEK 1 and MEK 2 enzymes without substantial inhibition of other such enzymes.
  • 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-[l]benzopyran.
  • the MEK inhibitor to be administered is a phenyl amine derivative of Formula I
  • R] is hydrogen, hydroxy, Cj-Cg alkyl, Ci -Cg alkoxy, halo, trifluoromethyl, or CN.
  • R2 is hydrogen.
  • R3, R4, and R5 are independently selected from hydrogen, hydroxy, halo, trifluoromethyl, Cj-Cg alkyl, C1 -Cg alkoxy, nitro, CN, and -(O or NH) m -(CH2) n -R9.
  • R9 is hydrogen, hydroxy,
  • Ri 0 and Rl 1 are 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-(C ⁇ -Cg alkyl).
  • Z is COOR7, tetrazolyl, CONRgRy, CONHNRioR-H, or CH 2 OR 7 .
  • Rg and R7 independently are hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, (CO)-C -Cg alkyl, aryl, heteroaryl, C3-C10 cycloalkyl, or C3-C10 (cycloalkyl optionally containing one, two, or three heteroatoms selected from O, S, NH, or N alkyl); or 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.
  • any of the foregoing alkyl, alkenyl, aryl, heteroaryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, -C 6 alkoxy, amino, nitro, C C 4 alkylamino, di(C]-C 4 )alkylamino, C 3 -C 6 cycloalkyl, phenyl, phenoxy, C 3 -C 5 heteroaryl or heterocyclic radical, or C 3 -C 5 heteroaryloxy or heterocyclic radical- oxy.
  • the invention also provides a pharmaceutically acceptable salt, ester, amide, or prodrug of each of the disclosed MEK inhibitors.
  • Preferred embodiments of Formula (I) have a structure wherein: (a) R is hydrogen, methyl, methoxy, fluoro, chloro, or bromo; (b) R 2 is hydrogen; (c) R 3 , R 4 , and R 5 independently are hydrogen, fluoro, chloro, bromo, iodo, methyl, methoxy, or nitro; (d) R 10 and Rn independently are hydrogen or methyl; (e) Z is COOR 7 , tetrazolyl, CONR 6 R 7 , CONHNR. 0 R n , or CH 2 OR 7 ; Re and R 7 independently are hydrogen, C 1 - 4 alkyl, heteroaryl, or C 3 .
  • the MEK inhibitor is selected from a compound in Formula (I) Compound Table below.
  • the MEK inhibitor is a compound of Formula II
  • R ⁇ a is hydrogen, hydroxy, Cj-Cg alkyl, Ci-C alkoxy, halo, trifluoromethyl, or CN.
  • R2 a is hydrogen.
  • RlO a and R j a is independently hydrogen or Ci-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-(C ⁇ -Cg alkyl).
  • R a is hydrogen, C ⁇ Cg alkyl, (CO)-(C ⁇ -Cg alkyl), aryl, aralkyl, or C3-C10 cycloalkyl.
  • R ⁇ a is hydrogen, Ci-Cg alkyl,
  • any of the foregoing alkyl, alkenyl, aryl, heteroaryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, C ⁇ -C 6 alkoxy, amino, nitro, CrC 4 alkylamino, di(C 1 -C 4 )alkylamino, C 3 -C 6 cycloalkyl, phenyl, phenoxy, C 3 -C 5 heteroaryl or heterocyclic radical, or C3-C5 heteroaryloxy or heterocyclic radical- oxy; or Rg a and R ⁇ a taken together with the N to which they are attached can complete a 5- to 10-membered cyclic ring, optionally containing one, two, or
  • Rj a is H, methyl, fluoro, or chloro
  • R 2a is H
  • R 3a , R 4a , and R 5a are each H, Cl, nitro, or F
  • R ⁇ a is H
  • R 7a is methyl, ethyl, 2-propenyl, propyl, butyl, pentyl, hexyl, cyclopropylmethyl, cyclobutyl methyl, cyclopropylmethyl, or cyclopropylethyl
  • the 4' position is I, rather than Br
  • R ⁇ is F at the 4 position, para to the CO-N-R ⁇ a -OR ⁇ group and meta to the bridging nitrogen;
  • R 3a or R 5a is F;
  • at least one of R 3a , R 4a , and R 5a is F;
  • R la is methyl or chloro; or (i) or a combination of the above.
  • the MEK inhibitor is a compound selected from Formula (II) Compound Table below.
  • a compound selected from the following is administered to a patient (ie, a mammal) in an amount that is effective to prevent or treat rheumatoid arthritis or osteoarthritis: 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy- 3,4-difluorobenzamide (PD184352); 2-(2-Methyl-4-iodophenylamino)-N- hydroxy-4-fluorobenzamide (PD 170611); 2-(2-Methyl-4-iodophenylamino)-N- hydroxy-3,4-difluoro-5-bromobenzarnide (PD171984); 2-(2-Methyl-
  • PD 203311 4-iodophenylamino)-N-cyclopropylmethoxy-4-fluorobenzamide
  • benzoic acid derivatives thereof For example, the benzoic acid derivative of PD 198306 is 2-(2 -Methyl -4-iodophenylamino)-3,4,5-trifluorobenzoic acid.
  • Additional preferred compounds include 2-(2-chloro-4-iodophenylamino)-5- chloro-N-cyclopropylmethoxy -3,4-difluorobenzamide (PD 297189), 2-(4- iodophenylamino)-N-cyclopropylmethoxy-5-chloro-3,4-difluorobenzamide (PD 297190), 2-(4-iodophenylamino)-5-chloro-3,4-difluorobenzoic acid (PD 296771), 2-(2-chloro-4-iodophenylamino)-5-chloro-3,4-difluorobenzoic acid (PD 296770),
  • the invention further provides methods of synthesis and synthetic intermediates as disclosed below.
  • 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 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.
  • 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.
  • 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, 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-oxo-4H-[l]benzopyran.
  • 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.
  • patient means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, horses, and pigs.
  • aryl means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from five to twelve carbon atoms.
  • typical aryl groups include phenyl, naphthyl, and fluorenyl.
  • the aryl may be substituted by one, two, or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino, or dialkylamino.
  • Typical substituted aryl groups include 3 -fluorophenyl, 3,5-dimethoxyphenyl, 4-nitronaphthyl, 2-methyl-4-chloro-7-aminofluorenyl, and the like.
  • 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.
  • 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.
  • substituted heteroaryl groups include chloropyranyl, methylthienyl, fluoropyridyl, amino- 1 ,4-benzisoxazinyl, nitroisoquinolinyl, and hydroxyindolyl.
  • heteroaryl groups can be bonded through oxygen to make heteroaryloxy groups, for example thienyloxy, isothiazolyloxy, benzofuranyloxy, pyridyloxy, and 4-methylisoquinolinyloxy.
  • alkyl means straight and branched chain aliphatic groups. Typical alkyl groups include methyl, ethyl, isopropyl, tert.-butyl,
  • 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, l,l-dimethyl-3-(2-nitrophenoxy)butyl, and 3,4,5-trifluoronaphthylmethyl.
  • Examples of alkyl groups substituted by a heteroaryl or heteroaryloxy group include thienylmethyl, 2-furylethyl, 6-furyloxyoctyl, 4-methylquinolyloxymethyl, and 6-isothiazolylhexyl.
  • Cycloalkyl substituted alkyl groups include cyclopropylmethyl, 2-cyclohexyethyl, piperidyl- 2-methyl, 2-(piperidin-l-yl)-ethyl, 3-(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.
  • 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-fiuorophenyl)-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.
  • 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.
  • 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,
  • 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.
  • a selective MEK 1 or MEK 2 inhibitor has an ICso for MEK 1 or MEK 2 that is at least one-fiftieth (1/50) that of its IC 50 for one of the above-named other enzymes.
  • a selective inhibitor has an IC 50 that is at least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/5000, or less than that of its IC 50 or one or more of the above- name enzymes.
  • 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
  • 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.
  • 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.
  • compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • 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.
  • 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.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate
  • solution retarders as for example paraffin
  • absorption accelerators as for example, quaternary ammonium compounds
  • wetting agents such as sodium citrate or dicalcium phosphate
  • fillers or extenders as for example
  • 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.
  • 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.
  • inert diluents commonly used in the art, such as water or other solvents, solubil
  • the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, macrocrystalline 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.
  • 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.
  • dosage levels in the range of about 0.1 to about 1000 mg per day.
  • a dosage in the range of about 0.01 to about 100 mg per kg of body weight per day is preferable.
  • the specific dosage used can vary.
  • 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.
  • pharmaceutically acceptable salts, esters, amides, and prodrugs 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.
  • 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.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium and the like
  • nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like See, for example, S.M. Berge, et al., "Pharmaceutical Salts.” J Pharm. Sci.. 1977;66:1-19 which is incorporated herein by reference.)
  • esters of the compounds of this invention examples include C -C6 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
  • 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.
  • 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 Biorevers ⁇ ble Carriers in Drug Desisn, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • 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.
  • 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.
  • 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.
  • 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.
  • a base such as lithium diisopropylamide, n-butyl lithium, sodium hydride, triethylamine, and Hunig's base.
  • the reaction generally is carried out at a temperature of about -78°C to about 100°C, and normally is complete within about 2 hours to about 4 days.
  • the product can be isolated by removing the solvent, for example by evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
  • the 2-(phenylamino)-benzoic acid (e.g., Formula I, where R7 is hydrogen) can be reacted with an organic or inorganic base such as pyridine, triethylamine, calcium carbonate, or sodium hydroxide to produce a pharmaceutically acceptable salt.
  • the free acids can also be reacted with an alcohol of the formula HOR7 (where R7 is other than hydrogen, for example methyl) to produce the corresponding ester.
  • Reaction of the benzoic acid with an alcohol can be carried out in the presence of a coupling agent.
  • Typical coupling reagents include 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline (EEDQ), 1,3-dicyclohexylcarbodiimide (DCC), bromo-tris(pyrrolidino)- phosphonium hexafluorophosphate (PyBrOP), and (benzotriazolyloxy) tripyrrolidino phosphonium hexafluorophosphate (PyBOP).
  • EEDQ 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline
  • DCC 1,3-dicyclohexylcarbodiimide
  • PyBrOP bromo-tris(pyrrolidino)- phosphonium hexafluorophosphate
  • PyBOP benzotriazolyloxy tripyrrolidino phosphonium hexafluorophosphate
  • 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 are readily prepared by reacting the foregoing benzoic acids with an amine of the formula HNR0R7.
  • the reaction is carried out by reacting approximately equimolar quantities of the benzoic acid and amine in an unreactive organic solvent in the presence of a coupling reagent.
  • Typical solvents are chloroform, dichloromethane, tetrahydrofuran, benzene, toluene, and xylene.
  • Typical coupling reagents include DCC, EEDQ, PyBrOP, and PyBOP. The reaction is generally complete after about 10 minutes to about 2 hours when carried out at a temperature of about 0°C to about 60°C.
  • the product amide is readily isolated by removing the reaction solvent, for instance by evaporation, and further purification can be accomplished by normal methods such as chromatography, crystallization, or distillation.
  • the benzyl alcohols of the invention, compounds of Formula I where Z is CH2OR and R is hydrogen, are readily prepared by reduction of the corresponding benzoic acid according to the following Scheme 2.
  • Typical reducing agents commonly employed include borane in tetrahydrofuran.
  • the reduction normally is carried out in an unreactive organic solvent such as tetrahydrofuran, and generally is complete within about 2 hours to about 24 hours when conducted at a temperature of about 0°C to about 40°C.
  • EXAMPLE 1 4-Fluoro-2-C4-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 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 ⁇ M spherical silica, pore size 115 A derivatized with C-18, the sample was eluted at 4.7 mL/min with a linear ramp to 100% acetonitrile over 8.5 minutes. Elution with 100% acetonitrile continued for 8 minutes). Fractions were collected by monitoring at 214 nM. The residue was dissolved in chloroform and transferred to a preweighed vial, evaporated, and weighed again to determine
  • Step b Preparation of 5-chloro-2-fluoro-benzaldehvde oxime
  • the 4-bromo and 4-iodo phenylamino benzhydroxamic acid derivatives of Formula II can be prepared from commercially available starting materials utilizing synthetic methodologies well-known to those skilled in organic chemistry.
  • a typical synthesis is carried out by reacting a 4-bromo or 4-iodo aniline with a benzoic acid having a leaving group at the 2-position to give a phenylamino benzoic acid, and then reacting the benzoic acid phenylamino derivative with a hydroxylamine derivative (Scheme 3), where L is a leaving group, for example halo such as fluoro, chloro, bromo or iodo, or an activated hydroxy group such as a diethylphosphate, trimethylsilyloxy, p-nitrophenoxy, or phenylsulfonoxy.
  • the reaction of aniline and the benzoic acid derivative generally is accomplished by mixing the benzoic acid with an equimolar quantity or excess of the aniline in an unreactive organic solvent such as tetrahydrofuran, or toluene, in the presence of a base such as lithium diisopropylamide, n-butyl lithium, sodium hydride, and sodium amide.
  • the reaction generally is carried out at a temperature of about -78°C to about 25°C, and normally is complete within about 2 hours to about 4 days.
  • the product can be isolated by removing the solvent, for example by evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
  • the phenylamino benzoic acid next is reacted with a hydroxylamine derivative HNRg a OR7 a in the presence of a peptide coupling reagent.
  • Hydroxylamine derivatives that can be employed include methoxylamine, N-ethyl-isopropoxy amine, and tetrahydro-oxazine.
  • Typical coupling reagents include 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline (EEDQ), 1 ,3-dicyclohexylcarbodiimide (DCC), bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP) and (benzotriazolyloxy)tripyrrolidino phosphonium hexafluorophosphate (PyBOP).
  • EEDQ 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline
  • DCC 1 ,3-dicyclohexylcarbodiimide
  • PyBrOP bromo-tris(pyrrolidino)-phosphonium hexafluorophosphat
  • the phenylamino benzoic acid and hydroxylamino derivative normally are mixed in approximately equimolar quantities in an unreactive organic solvent such as dichloromethane, tetrahydrofuran, chloroform, or xylene, and an equimolar quantity of the coupling reagent is added.
  • a base such as triethylamine or diisopropylethylamine can be added to act as an acid scavenger if desired.
  • the coupling reaction generally is complete after about 10 minutes to 2 hours, and the product is readily isolated by removing the reaction solvent, for instance by evaporation under reduced pressure, and purifying the product by standard methods such as chromatography or crystallizations from solvents such as acetone, diethyl ether, or ethanol.
  • An alternative method for making the invention compounds involves first converting a benzoic acid to a hydroxamic acid derivative, and then reacting the hydroxamic acid derivative with an aniline.
  • This synthetic sequence is depicted in Scheme 4, where L is a leaving group.
  • the general reaction conditions for both of the steps in Scheme 4 are the same as those described above for Scheme 3.
  • Yet another method for making invention compounds comprises reacting a phenylamino benzhydroxamic acid with an ester forming group as depicted in Scheme 5, where L is a leaving group such as halo, and a base is triethylamine or diisopropylamine.
  • Examples 3 a to 12a in the table below were prepared by the general procedure of Examples la and 2a.
  • 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.
  • ANUS screen This screen is designed to identify compounds which inhibit HSV-1 in phases of its life cycle from adsorption and penetration through late gene expression.
  • the primary screen, ANUS1 involves adding single compounds to a monolayer of Vero cells to a final concentration of 25 ⁇ g/mL, then infecting the cells with a recombinant HSN-1, Us3::Tn5-lacZ.
  • This virus contains an insertion of a lacZ gene driven by a viral late promoter in the US3 protein kinase gene of HSV-1. The infection is allowed to proceed for 20 hours, then the cells are lysed with a solution of Triton X-100 and CPRG in "Z" buffer and assayed for ⁇ -galactosidase activity.
  • the positive control used is solvent alone without test compound, which corresponds to 0% inhibition
  • the negative control used is either no virus added to the wells or 0.5% Triton X-100 added to the wells, which corresponds to 100% inhibition. Percent inhibition of viral growth is then calculated using the positive and the negative controls.
  • Test compounds which cause at least an 80% inhibition in the AVUS 1 assay are carried forward into a secondary screen, AVUS2, in which a titration of the compound from the frozen diluted stock of the AVUS1 screen is assayed for inhibition of HSV-1 via the same ⁇ -galactosidase and toxicity via a 1-day XTT assay in the absence of virus.
  • AVUS2 secondary screen
  • Those compounds which have good activities ( ⁇ 2 ⁇ g/mL), good therapeutic indices (> 10-fold), and which are not planar compounds are then carried forward into a tertiary screen termed AVUS3.
  • AVUS3 assay the test compound is dissolved in MeOH at 20 nM. A titration of the compound is then assayed in both the same ⁇ -galactosidase virus replication inhibition assay, and a 5-day XTT toxicity assay.
  • follow-up screens to this core set of AVUS screens include plaque reduction and yield reduction assays with wild-type HSV-1 to verify antiviral activity, and time course of addition studies to begin to dissect a possible mechanism of action.
  • HCMV human cytomegleovirus
  • HSV-1 herpesvirus
  • Table 1 below presents the results of such assays for several of the compounds described above.
  • IC50 the concentration of test compound required to inhibit viral growth by 50%
  • TC50 the concentration of test compound which killed 50% of the cells.
  • the selective MEK inhibitors have been evaluated in standard assays to determine their ability to prevent and treat HIV infections.
  • One of the assays used to determine the activity against the HIV virus is that employed by the US national Cancer Institute as described by Weislow et al., J Natl. Cancer Inst., 1989; 81:577-586, incorporated herein by reference.
  • Other assays commonly used include the MTT cell culture assays using CEM or MT2 cells. This assay involves the conversion of the tetrazolium dye MTT to a colored formazan product by mitochondrial enzymes in metabolically active cells. These assays are routinely used by Southern Research Institute (SRI) in an established program for determining primary antiviral activity of compounds.
  • SRI Southern Research Institute
  • the Weislow et al procedure is described below.
  • the procedure is designed to detect agents acting at any stage of the virus reproductive cycle.
  • the assay basically involves the killing of T4 lymphocytes by HIV. Small amounts of HIV are added to cells, and at least two complete cycles of virus reproduction are necessary to obtain the required cell killing. Agents which interact with virions, cells, or virus gene-products to interfere with viral activities will protect cells from cytolysis.
  • the system is automated in several features to accommodate large numbers of candidate agents, and is generally designed to detect anti-HIV activity. However, compounds which degenerate or are rapidly metabolized in the culture conditions may not show activity in this screen.
  • Another test system utilized to evaluate the invention compounds is called
  • HIV H9 assay The HIV H9 cell assay measures the inhibitor concentration required to suppress HIV-1 virus replication. In this system, viral growth occurs through multiple rounds of the life-cycle. Any suppression of the replication kinetics results in a geometric decrease in virus production. As a result, this assay is a sensitive means of measuring the ability of a compound to inhibit HIV-1 viral replication.
  • the H9 T-cell line is batch infected with HIV virus at an MOI of 0.01. After 2 hours absorption, the cells are washed, resuspended in RPMI- 1640/10% fetal calf serum, and seeded at 5 x 10-3 cells/well of a 96-well plate. A duplicate plate of uninfected H9 cells is prepared for the cytotoxicity assay. Drugs are serially diluted 1/3.16 in DMSO, transferred to media at a x8 concentration, and then added to the cultures in triplicate. The final DMSO concentration of 0.002 (0.2%).
  • Viral production is measured by RT assay and cytotoxicity is measured by XTT assay at 7 days post-infection.
  • the RT assay is performed as a modification of Borroto-Esoda and Boone, J. Virol., 1991;65:1952-1959 and quantitated using a Molecular Dynamics Phosphoimager with Imagequant software.
  • the XTT assay is performed as a modification of Roehm, et al., J. Immuno. Methods., 1991;142:257-265 and quantitated using a molecular Devices Thermomax plate reader with Softmax software.
  • RT assay values equivalent to 50% and 90% inhibition of virus production are calculated from the untreated controls.
  • concentrations of inhibitor required to produce these values (IC50 and IC90) are interpolated from data points flanking these RT activities.
  • the XTT assay values equivalent to 50% cytotoxicity are calculated from the untreated controls.
  • the concentrations of inhibitor required to produce this value are interpolated from data points flanking these XTT values.
  • CEM cell assay Yet another test system employed to determine antiviral activity is called the CEM cell assay.
  • T4 lymphocytes (CEM cell line) are exposed to HIV at a virus to cell ratio approximately 0.05, and plated along with noninfected control cells in 96-well microliter plates.
  • Candidate agent is dissolved in dimethyl sulfoxide (unless otherwise noted), then diluted 1 :200 in cell culture medium. Further dilutions (half-log 10) are prepared before adding to an equal volume of medium containing either infected or noninfected cells.
  • Cultures are incubated at 37° in a 5% carbon dioxide atmosphere for 6 or 7 days.
  • the tetrazolium salt, XTT is added to all wells, and cultures are incubated to allow formazan color development by viable cells J. National Cancer Institute, 1989;81 :577-586.
  • Individual wells are analyzed spectrophotometrically to quantitate formazan production, and in addition are viewed microscopically for detection of viable cells confirmation of protective activity.
  • Drug-tested virus-infected cells are compared with drug-treated noninfected cells and with other appropriate controls (untreated infected and untreated noninfected cells, drug-contain wells without cells, etc.) on the same plate. Data are reviewed in comparison with other tests done at the same time and a determination about activity is made.
  • Table 2 shows the anti-HIV activity of several selective MEK inhibitors.
  • the Table presents EC50 ( CEMss-HIV 1 Rf) and TC 50 values.
  • 0184161 toxic > 6.25 ⁇ M 6.0 ⁇ M 8.5 ⁇ M
  • 0180841 toxic > 6.25 ⁇ M 6.0 ⁇ M 6.1 ⁇ M
  • Compound 177168 gave an excellent dose response with the rest being flat liners in regards to antiviral activity. Testing against Ba-L in macrophages is ongoing and data will be available in about 10 days.
  • MEK inhibitors are active in both preventing a viral infection and in controlling or treating a disease caused by a viral infection.
  • the compounds are therefore useful in the prophylaxis of diseases such as cold sores (caused by herpes simplex 1) and genital herpes, and also in treating and alleviating the symptoms that accompany diseases caused by viruses during their active stage of infection.
  • Typical viral infections to be prevented and treated according to this invention include HIV, Hepatitis B, papalomavirus, and reovirus.
  • the compounds have little or no toxic effects, and accordingly are particularly well-suited for treating and controlling viral infections in children, including AIDS, as well as adults.
  • the compounds will be formulated for convenient oral or parenteral administration, including by aerosol delivery, transdermal delivery, or even suppositories, and will be administered in an antivirally effective dose, which is that amount that is effective to prevent and/or treat the particular virus and its severity for which treatment is needed or otherwise desired.
  • the compounds will be formulated as a topical cream, or as oral capsules and administered form one to three times a day to an individual who is engaging in activities which may lead to a viral infection. Such activities include being exposed to large amounts of ultraviolet sun radiation, which often precipitates activation of herpes simplex 1, resulting in cold sores, particularly in and around the mouth.
  • the disclosed MEK inhibitors can also be used in combination with other clinically effective antiviral agents. Such combination therapy has been found particularly useful for treating patients suffering from HIV infections.
  • Agents which will be commonly used in combination with the MEK inhibitors include acyclovir, AZT (azidothymidine, zidovudine), ribavirin, vidarabine, ganciclovir, dideoxyinosine (ddl), and any of a number of protease inhibitors such as nelfinavir mesylate, and retroviral antigens such as remune (described in US 5,256,767, incorporated herein by reference).
  • the Bal antiviral activities shown in Table 3 establish that several of the MEK inhibitors have excellent antiviral efficacy.
  • Particularly preferred compounds to be used to treat and prevent HIV infections are 2-(2-chloro- 4-iodophenylamino)-N-cyclobutylmethoxy-3,4-difluorobenzamide (PD 185625); 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-4-fluorobenzamide (PD 203311); 2-(2-chloro-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD 185848); and 2-(2-methyl-4-iodophenylamino)-N-cyclopropylmethoxy-3,4,5- rifluorobenzamide (PD 198306).
  • These MEK inhibitors have excellent antiviral activity in the absence of cytotoxicity.
  • One aspect of the invention features a method for treating or preventing a viral infection, wherein said method includes administering a MEK inhibitor before a viral infection in the patient has been confirmed.
  • the HIV BaL/Macro data in Table 3 was obtained by adding the MEK inhibitor following activation but before HIV infection.

Abstract

This invention provides a method of preventing or treating viral infections by administering to a patient in need of treatment an effective amount of a MEK inhibitor, especially a phenyl amine of Formula (I) and (II).

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-[l]benzopyran.
In another preferred embodiment, the MEK inhibitor to be administered is a phenyl amine derivative of Formula I
In Formula (I), R] is hydrogen, hydroxy, Cj-Cg alkyl, Ci -Cg alkoxy, halo, trifluoromethyl, or CN. R2 is hydrogen. R3, R4, and R5 are independently selected from hydrogen, hydroxy, halo, trifluoromethyl, Cj-Cg alkyl, C1 -Cg alkoxy, nitro, CN, and -(O or NH)m-(CH2)n-R9. R9 is hydrogen, hydroxy,
COOH, or NRj QRI 1 ; n is 0-4; m is 0 or 1. Each of Ri 0 and Rl 1 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-(Cι-Cg alkyl). Z is COOR7, tetrazolyl, CONRgRy, CONHNRioR-H, or CH2OR7. Rg and R7 independently are hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, (CO)-C -Cg alkyl, aryl, heteroaryl, C3-C10 cycloalkyl, or C3-C10 (cycloalkyl optionally containing one, two, or three heteroatoms selected from O, S, NH, or N alkyl); or 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, -C6 alkoxy, amino, nitro, C C4 alkylamino, di(C]-C4)alkylamino, C3-C6 cycloalkyl, phenyl, phenoxy, C3-C5 heteroaryl or heterocyclic radical, or C3-C5 heteroaryloxy or heterocyclic radical- oxy. The invention also provides a pharmaceutically acceptable salt, ester, amide, or prodrug of each of the disclosed MEK inhibitors.
Preferred embodiments of Formula (I) have a structure wherein: (a) R is hydrogen, methyl, methoxy, fluoro, chloro, or bromo; (b) R2 is hydrogen; (c) R3, R4, and R5 independently are hydrogen, fluoro, chloro, bromo, iodo, methyl, methoxy, or nitro; (d) R10 and Rn independently are hydrogen or methyl; (e) Z is COOR7, tetrazolyl, CONR6R7, CONHNR.0Rn, or CH2OR7; Re and R7 independently are hydrogen, C 1-4 alkyl, heteroaryl, or C 3.5 cycloalkyl optionally containing one or two heteroatoms selected from O, S, or NH; or Re 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 COOR7; (g) R7 is H, pentafluorophenyl, or tetrazolyl; (h) R3, R^ and R5 are independently H, fluoro, or chloro; (i) R4 is fluoro; (j) two of R3, R4, and R5 are fluoro; or (k) combinations of the above. In another preferred embodiment of Formula (I), Ri 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 l of 10)
[4-Chloro-2-( 1 H-tetrazol-5 -yl)-phenyl-(4-iodo-2-methyl-phenyl)-amine (4-iodo-2-methyl-phenyl)-[2-(lH-tetrazol-5-yl)-phenyl]amine
[4-nitro-2-(lH-tetrazol-5-yl)-phenyl-(4-iodo-2-methyl-phenyl)-amine
4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid
3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
Sodium 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoate
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic acid 4-Chloro-2-(4-iodo-2 -methyl -phenylamino)-benzoic acid
2-(4-Iodo-2-methyl-phenylamino)-benzoic acid
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
2,3, 5-Trifluoro-4-(4-iodo-2-methyl-phenylamino)-benzoic acid 2-(4-Iodo-phenylamino)-5-methoxy-benzoic acid
5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
2-(4-Iodo-2-methyl-phenylamino)-4-nitro-benzoic acid
2-(4-Bromo-2-methyl-phenylamino)-4-fluoro-benzoic acid
2-(2-Bromo-4-iodo-phenylamino)-5 -nitro-benzoic acid 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-benzόic acid
5-Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-benzamide
N-Ethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(lH-tetrazol-5-yl)-benzamide FORMULA (I) COMPOUND TABLE (continued, page 2 of 10)
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide
[5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoylamino]-acetic acid 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-propyl-benzamide 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
4-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-propyl}-2-(4-iodo-
2-methyl-phenylamino)-benzamide N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide N-Butyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N,N-diethyl-2-(4-iodo-2-methyl-phenylamino)-benzamide
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide 5-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide N-(2,3-Dihydroxy-propyl)-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-l- yl-ethyl)-benzamide 3,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide N-(2,3-Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide 3,4-Difluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5 -Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 1 - yl-ethyl)-benzamide
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- ethyl)-benzamide FORMULA (I) COMPOUND TABLE (continued, page 3 of 10)
4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide 5 -Bromo-N-(3 -dimethylamino-propyl)-3 ,4-difluoro-2-(4-iodo-
2-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-l-yl-propyl)- benzamide
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thiophen-2-yl-ethyl)- benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-l-yl-ethyl)- benzamide 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-N-(2-morpholin-4-yl- ethyl)-benzamide FORMULA (I) COMPOUND TABLE (continued, page 4 of 10)
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4- ylmethyl-benzamide
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide 2-(4-Bromo-2-methyl-phenylamino)-N-(3-dimethylamino- propyl) -3 ,4-difluoro-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl-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 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-l-yl- ethyl)- benzamide 5-Chloro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-propyl}-2-(4-iodo-2- methyl- phenylamino)- benzamide 5 -Fluoro-N- { 3 - [4-(2-hydroxy-ethyl)-piperazin- 1 -yl] -propyl } -2-(4-iodo-2- methyl- phenylamino)- benzamide
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl methyl-benzamide FORMULA (I) COMPOUND TABLE (continued, page 5 of 10)
5-Bromo-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-propyl}-2-(4-iodo-2- methyl- phenylamino)- benzamide
5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-l-yl-ethyl)- benzamide (3-Hydroxy-pyrrolidin-l-yl)-[5-nitro-2-(4-iodo-2-methyl-phenylamino)-phenyl}- methanone
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-l-yl-ethyl)- benzamide 5-Bromo-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-chloro-2-(4-iodo-2-methyl- phenylamino)- benzamide N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-bromo-2-(4-iodo-2-methyl- phenylamino)- benzamide N- { 3 - [4-(2-Hydroxy-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-l-yl-ethyl)- benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl-ethyl)- benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-l-yl-ethyl)- benzamide 5-Chloro-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-fluoro-2-(4-iodo-2-methyl- phenylamino)- benzamide FORMULA (I) COMPOUND TABLE (continued, page 6 of 10)
5-Chloro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
5-Chloro-N-(3-diethylamino-2-hydroxy-propyl)-2-(4-iodo-2-methyl- phenylamino)- benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-l-yl-ethyl)- benzamide 5-Bromo-N-(3 -hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl-propyl)- benzamide N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-2-(4-iodo-2-methyl- phenylamino)-5-nitro- benzamide
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-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-l-yl-propyl)- benzamide 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin-l-yl-ethyl)- benzamide
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin-l-yl-ethyl)- benzamide N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 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 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-l-yl-propyl)- benzamide [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(2 or 3-hydroxy- pyrrolidin-l-yl)-methanone
5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)- benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl-propyl)- benzamide [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4-(2-hydroxy-ethyl)- piperazin- 1 -yl)-methanone N-(3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)- benzamide
N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide FORMULA (I) COMPOUND TABLE (continued, page 8 of 10)
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide
5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide N-(2-Hydroxy-ethyl)-2-(4-iodo-2-ethyl-phenylamino)-5-nitro-benzamide 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl-benzamide
5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5 -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide N-AUyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide
N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide FORMULA (I) COMPOUND TABLE (continued, page 9 of 10)
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Allyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-benzamide 2-(4-Iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-5-nitro-benzamide 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide
N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide 5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-benzamide
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl-benzamide
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide FORMULA (I) COMPOUND TABLE (continued, page 10 of 10)
N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide
5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide 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)-pheny 1] -methanol [2-(4-Iodo-2-methyl-phenylamino)-5-nitro-phenyl]-methanol [5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide.
In another preferred embodiment, the MEK inhibitor is a compound of Formula II
In Formula (II), Rιa is hydrogen, hydroxy, Cj-Cg alkyl, Ci-C alkoxy, halo, trifluoromethyl, or CN. R2a is hydrogen. Each of R3a, R4a, and R5a is independently selected from hydrogen, hydroxy, halo, trifluoromethyl, Ci-Cg alkyl, Ci-C alkoxy, nitro, CN, and (O or NH)m-(CH2)n-R9a- R-9a is hydrogen, hydroxy, CO2H or NRiQaRι ιa; n is 0-4; and m is 0 or 1. Each of RlOa and R ja is independently hydrogen or Ci-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3- to 10-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S, NH, or N-(Cι-Cg alkyl). R a is hydrogen, C^Cg alkyl, (CO)-(Cι-Cg alkyl), aryl, aralkyl, or C3-C10 cycloalkyl. Rγa is hydrogen, Ci-Cg alkyl,
C2-C alkenyl, C2-Cg alkynyl, C3-C10 (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NR9a). In Formula (II), any of the foregoing alkyl, alkenyl, aryl, heteroaryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, Cι-C6 alkoxy, amino, nitro, CrC4 alkylamino, di(C1-C4)alkylamino, C3-C6 cycloalkyl, phenyl, phenoxy, C3-C5 heteroaryl or heterocyclic radical, or C3-C5 heteroaryloxy or heterocyclic radical- oxy; or Rga and Rγa 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 NRιøaRι ja. 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) Rja is H, methyl, fluoro, or chloro; (b) R2a is H; R3a, R4a, and R5aare each H, Cl, nitro, or F; (c) Rόa is H; (d) R7a is methyl, ethyl, 2-propenyl, propyl, butyl, pentyl, hexyl, cyclopropylmethyl, cyclobutyl methyl, cyclopropylmethyl, or cyclopropylethyl; (e) the 4' position is I, rather than Br; (f) R^ is F at the 4 position, para to the CO-N-Rόa-OR^ group and meta to the bridging nitrogen;
(f) R3a or R5a is F; (g) at least one of R3a, R4a, and R5a is F; (h) Rla is methyl or chloro; or (i) or a combination of the above.
In a more preferred embodiment the MEK inhibitor is a compound selected from Formula (II) Compound Table below. FORMULA (II) COMPOUND TABLE (page 1 of 7)
-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(methoxy)-benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)-benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)-benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thienylmethoxy)-benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-enyloxy)-benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropylmethoxy)-benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopentoxy)-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-furylmethoxy)-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-ethoxy-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropylmethoxy)- benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-( 1 -methylprop-2-yny loxy)- benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -phenylprop-2-ynyloxy)- benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-5-phenylpent-2-en-
4-ynyloxy)-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(propoxy)-benzamide
FORMULA (II) COMPOUND TABLE (continued, page 2 of 7) ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclobutyloxy)-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thienylmethoxy)-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-methyl-prop-2-enyloxy)- benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-3-ynyloxy)-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopentyloxy)-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-(2-fluorophenyl)-prop-
2-ynyloxy)-benzamide -Bromo-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(n-propoxy)- benzamide -Bromo-3 ,4-difluoro-N-(furan-3 -ylmethoxy)-2-(4-iodo-2-methyl-phenylamino)- benzamide -Bromo-N-(but-2-enyloxy)-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide -Bromo-N-butoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-but-
2-enyloxy)-benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-pent-2-en- 4-ynyloxy)-benzamide
FORMULA (II) COMPOUND TABLE (continued, page 3 of 7) -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-benzyl)-N-[5-(3-methoxy-phenyl)- 3 -methy l-pent-2-en-4-ynyloxy] -benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)- benzamide -Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- [3 -(3 -methoxy- phenyl)-prop-2-ynyloxy]-benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(thiopen-
2-ylmethoxy)-benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(pyridin-
3 -ylmethoxy)-benzamide -Bromo-3-4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-(2-fluorophenyl)- prop-2-ynyloxy)-benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(ethoxy)-benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(cyclopropylmethoxy)-benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(isopropoxy)- benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-but-3-ynyloxy)- benzamide -Chloro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide -Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydro-pyran-2-yloxy)- benzamide -Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy-benzamide -Bromo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide -Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide -Iodo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydropyran-2-yloxy)- benzamide FORMULA (II) COMPOUND TABLE (continued, page 4 of 7) ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3-phenylprop-2-ynyloxy)- benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3-furylmethoxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-thienylmethoxy)- benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but-3-ynyloxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-methyl-prop-2-enyloxy)- benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but-2-enyloxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(methoxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(ethoxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclobutoxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(isopropoxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)- benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclopropylmethoxy)- benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(n-propoxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(1-methyl-prop-2-ynyloxy)- benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3-(3-fluorophenyl)-prop- 2-ynyloxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(4,4-dimethylpent- 2-ynyloxy)-benzamide
FORMULA (II) COMPOUND TABLE (continued, page 5 of 7)
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclopentoxy)-benzamide 3,4,5-Trifluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide
5-Chloro-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide N-Hydroxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzamide 3,4,5-Trifluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide 5 -Chloro-3 ,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-benzamide 2-(2-Fluoro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide 2-(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy-benzamide 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-benzamide 5-Bromo-2-(2-bromo-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-benzamide
2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-methyl-benzamide 2-(2-Bromo-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy-benzamide 2-(2-Bromo-4-iodo-phenylamino)-5-chloro-3,4-difluoro-N-hydroxy-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide 4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-benzamide 2-(2-Bromo-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide -(2-Bromo-4-iodo-phenylamino)-3 ,4-difluoro-N-hydroxy-benzamide
FORMULA (II) COMPOUND TABLE (continued, page 6 of 7)
N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide
5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide N-Cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzamide
N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide 5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide N-Cyclopropylmethoxy-2-(2-fluoro-4-iodo-phenylamino)-4-nitro-benzamide 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4,5-trifluoro- benzamide 5 -Chloro-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3 ,4-difluoro- benzamide 5-Bromo-2-(2-bromo-4-iodo-phenylamino)-N-ethoxy-3,4-difluoro-benzamide 2-(2-Chloro-4-iodo-phenylamino)-N-ethoxy-4-nitro-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4,5-trifluoro- benzamide
2-(2-Bromo-4-iodo-phenylamino)-5-chloro-N-cyclopropylmethoxy-3,4-difluoro- benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-nitro-benzamide FORMULA (II) COMPOUND TABLE (continued, page 7 of 7)
N-Cyclopropylmethoxy-4-fluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide N-Cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro-benzamide 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide.
In the most preferred embodiment of this invention, a compound selected from the following is administered to a patient (ie, a mammal) in an amount that is effective to prevent or treat rheumatoid arthritis or osteoarthritis: 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy- 3,4-difluorobenzamide (PD184352); 2-(2-Methyl-4-iodophenylamino)-N- hydroxy-4-fluorobenzamide (PD 170611); 2-(2-Methyl-4-iodophenylamino)-N- hydroxy-3,4-difluoro-5-bromobenzarnide (PD171984); 2-(2-Methyl-
4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-bromobenzamide (PD 177168); 2-(2-Methyl-4-iodophenylamino)-N-cyclobutylmethoxy- 3,4-difluoro-5-bromobenzamide (PD 180841); 2-(2-Chloro-4-iodophenylamino)- N-cyclopropylmethoxy-3,4-difluoro-5-bromobenzamide (PD 184161); 2-(2-Chloro-4-iodophenylamino)-N-hydroxy-3,4-difluoro-5-bromobenzamide
(PD184386); 2-(2-Chloro-4-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-difluorobenzamide (PD 297189), 2-(4- iodophenylamino)-N-cyclopropylmethoxy-5-chloro-3,4-difluorobenzamide (PD 297190), 2-(4-iodophenylamino)-5-chloro-3,4-difluorobenzoic acid (PD 296771), 2-(2-chloro-4-iodophenylamino)-5-chloro-3,4-difluorobenzoic acid (PD 296770),
5-chloro-3,4-difluoro-2-(4-iodo-2-methylphenylamino)-benzoic acid (PD 296767); and 5-chloro-N-cyclopropylmethoxy -3,4-difluoro-2-(4-iodo-2- methylphenylamino)-benzamide (PD 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 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, 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-oxo-4H-[l]benzopyran. Specifically, a compound is a MEK inhibitor if a compound shows activity in the assay titled "Cascade Assay for Inhibitors of the MAP Kinase Pathway," column 6, line 36 to column 7, line 4 of the United States
Patent Number 5,525,625 and/or shows activity in the assay titled "In Vitro MEK Assay" at column 7, lines 4 to 27 of the above-referenced patent.
A. Terms Some of the terms used herein are defined below 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-nitronaphthyl, 2-methyl-4-chloro-7-aminofluorenyl, and the like.
The term "aryloxy" means an aryl group bonded through an oxygen atom, for example phenoxy, 3-bromophenoxy, naphthyloxy, and 4-methyl- 1-fluorenyloxy.
"Heteroaryl" means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from four to eleven carbon atoms and one, two, or three heteroatoms selected from O, S, or N. Examples include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, xanthenyl, pyronyl, indolyl, pyrimidyl, naphthyridyl, pyridyl, benzinnidazolyl, and triazinyl. The heteroaryl groups can be unsubstituted or substituted by one, two, or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino, or dialkylamino. Examples of substituted heteroaryl groups include chloropyranyl, methylthienyl, fluoropyridyl, amino- 1 ,4-benzisoxazinyl, nitroisoquinolinyl, and hydroxyindolyl.
The heteroaryl groups can be bonded through oxygen to make heteroaryloxy groups, for example thienyloxy, isothiazolyloxy, benzofuranyloxy, pyridyloxy, and 4-methylisoquinolinyloxy.
The term "alkyl" means straight and branched chain aliphatic groups. Typical alkyl groups include methyl, ethyl, isopropyl, tert.-butyl,
2,3-dimethylhexyl, and 1,1-dimethylpentyl. The alkyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, as those terms are defined herein. Typical substituted alkyl groups include chloromethyl, 3-hydroxypropyl, 2-dimethylaminobutyl, and 2-(hydroxymethylamino)ethyl. Examples of aryl and aryloxy substituted alkyl groups include phenylmethyl, 2-phenylethyl, 3-chlorophenylmethyl, l,l-dimethyl-3-(2-nitrophenoxy)butyl, and 3,4,5-trifluoronaphthylmethyl. Examples of alkyl groups substituted by a heteroaryl or heteroaryloxy group include thienylmethyl, 2-furylethyl, 6-furyloxyoctyl, 4-methylquinolyloxymethyl, and 6-isothiazolylhexyl. Cycloalkyl substituted alkyl groups include cyclopropylmethyl, 2-cyclohexyethyl, piperidyl- 2-methyl, 2-(piperidin-l-yl)-ethyl, 3-(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-fiuorophenyl)-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-l-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 ICso for MEK 1 or MEK 2 that is at least one-fiftieth (1/50) that of its IC50 for one of the above-named other enzymes. Preferably, a selective inhibitor has an IC50 that is at least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/5000, or less than that of its IC50 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, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well- known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, macrocrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like. Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalamic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
The compounds of the present method can be administered to a patient at dosage levels in the range of about 0.1 to about 1000 mg per day. For a normal human adult having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kg of body weight per day is preferable. The specific dosage used, however, can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well- known to those skilled in the art.
The compounds of the present method can be administered as pharmaceutically acceptable salts, esters, amides, or prodrugs. The term "pharmaceutically acceptable salts, esters, amides, and prodrugs" as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
The term "salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts, and the like.
These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, S.M. Berge, et al., "Pharmaceutical Salts." J Pharm. Sci.. 1977;66:1-19 which is incorporated herein by reference.)
Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include C -C6 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-C6 alkyl amines and secondary C\-C 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 Bioreversϊble Carriers in Drug Desisn, 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 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
base
where L is a leaving group, for example halo such as fluoro.
The reaction of aniline and the benzoic acid derivative generally is accomplished by mixing the benzoic acid with an equimolar quantity or excess of the aniline in an unreactive organic solvent such as tetrahydrofuran or toluene, in the presence of a base such as lithium diisopropylamide, n-butyl lithium, sodium hydride, triethylamine, and Hunig's base. The reaction generally is carried out at a temperature of about -78°C to about 100°C, and normally is complete within about 2 hours to about 4 days. The product can be isolated by removing the solvent, for example by evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
The 2-(phenylamino)-benzoic acid (e.g., Formula I, where R7 is hydrogen) can be reacted with an organic or inorganic base such as pyridine, triethylamine, calcium carbonate, or sodium hydroxide to produce a pharmaceutically acceptable salt. The free acids can also be reacted with an alcohol of the formula HOR7 (where R7 is other than hydrogen, for example methyl) to produce the corresponding ester. Reaction of the benzoic acid with an alcohol can be carried out in the presence of a coupling agent. Typical coupling reagents include 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline (EEDQ), 1,3-dicyclohexylcarbodiimide (DCC), bromo-tris(pyrrolidino)- phosphonium hexafluorophosphate (PyBrOP), and (benzotriazolyloxy) tripyrrolidino phosphonium hexafluorophosphate (PyBOP). The phenylamino benzoic acid and alcohol derivative normally are mixed in approximately equimolar quantities in an unreactive organic solvent such as dichloromethane, tetrahydrofuran, chloroform, or xylene, and an equimolar quantity of the coupling reagent is added. A base such as triethylamine or diisopropylethylamine can be added to act as an acid scavenger if desired. The coupling reaction generally is complete after about 10 minutes to 2 hours, and the product is readily isolated by removing the reaction solvent, for instance by evaporation under reduced pressure, and purifying the product by standard methods such as chromatography or crystallizations from solvents such as acetone, diethyl ether, or ethanol.
The benzamides of the invention, Formula I where Z is CONR R7, are readily prepared by reacting the foregoing benzoic acids with an amine of the formula HNR0R7. The reaction is carried out by reacting approximately equimolar quantities of the benzoic acid and amine in an unreactive organic solvent in the presence of a coupling reagent. Typical solvents are chloroform, dichloromethane, tetrahydrofuran, benzene, toluene, and xylene. Typical coupling reagents include DCC, EEDQ, PyBrOP, and PyBOP. The reaction is generally complete after about 10 minutes to about 2 hours when carried out at a temperature of about 0°C to about 60°C. The product amide is readily isolated by removing the reaction solvent, for instance by evaporation, and further purification can be accomplished by normal methods such as chromatography, crystallization, or distillation. The hydrazides (z = CONHNRIQRI l) are similarly prepared by coupling a benzoic acid with a hydrazine of the formula H2HNRIORΠ. The benzyl alcohols of the invention, compounds of Formula I where Z is CH2OR and R is hydrogen, are readily prepared by reduction of the corresponding benzoic acid according to the following Scheme 2.
Scheme 2
Typical reducing agents commonly employed include borane in tetrahydrofuran. The reduction normally is carried out in an unreactive organic solvent such as tetrahydrofuran, and generally is complete within about 2 hours to about 24 hours when conducted at a temperature of about 0°C to about 40°C.
The following detailed examples illustrate specific compounds provided by this invention.
EXAMPLE 1 4-Fluoro-2-C4-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 HC1 (10%) was added to the concentrate, and the solution was extracted with dichloromethane. The organic phase was dried (MgSO-i) and then boiled over a steambath to low volume and cooled to room temperature. The off-white fibers were collected by vacuum filtration, rinsed with hexanes, and vacuum-oven dried. (76°C; ca. 10 mm of Hg) to afford 1.10 g (47%) of the desired material; mp 224-229.5°C;
!H NMR (400 MHz; DMSO): δ 9.72 (s, IH), 7.97 (dd, IH, J = 7.0, 8.7 Hz), 7.70 (d, IH, J = 1.5 Hz), 7.57 (dd, IH, J = 8.4, 1.9 Hz), 7.17 (d, IH, J = 8.2 Hz),
6.61-6.53 (m, 2H), 2.18 (s, 3H); 13C NMR (100 MHz; DMSO): δ 169.87, 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;
!9F NMR (376 MHz; DMSO): δ -104.00 to -104.07 (m); IR (KBr) 1670 (C = O stretch) cm" l ;
MS (CI) M+l = 372. Analysis calculated for C14H11FINO2: C, 45.31; H, 2.99; N, 3.77.
Found: C, 45.21; H, 2.77; N, 3.64.
EXAMPLES 2-30 By following the general procedure of Example 1 , the following benzoic acids and salts of Formula (I) were prepared.
Example Compound MP °C
No.
2 3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)- 206-210 benzoic acid
3 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic 240.5-244.5 acid
4 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 259.5-262 phenylamino)-benzoic acid
5 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-benzoic acid 255-260
6 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 234-238
7 Sodium 5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 310-320 DEC benzoate
8 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 239.5-240
9 2-(2-Chloro-4-iodo-phenylamino)-5-nitro-benzoic acid 289-293
10 4-Fluoro-2-(3-fluoro-4-iodo-2-methyl-phenylamino)- 233-235 benzoic acid
11 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic acid 264-267
12 2-(2-Fluoro-4-iodo-phenylamino)-5-nitro-benzoic acid 256-258
13 2-(4-Bromo-2-methyl-phenylamino)-4-fluoro-benzoic 218.5-220 acid
14 2-(2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic acid 285-288 DEC
15 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro- 230-234 benzoic acid
16 3-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 218-221
17 3,4-Difluoro-2-(4-iodo-2-methoxy-phenylamino)- 230-233 benzoic acid
18 4-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 245-255 DEC
Example Compound MP °C No.
19 2-(4-Iodo-2-methyl-phenylamino)-benzoic acid 218-223
20 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 243-46
21 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 241-245
22 2,3,5-Trifluoro-4-(4-iodo-2-methyl-phenylamino)- 218-222 benzoic acid
23 4-Fluoro-2-(3-chloro-4-iodo-2-methyl-phenylamino)- 248-252.5 benzoic acid
24 2-(4-Iodo-phenylamino)-5-methoxy-benzoic acid 208-211
25 3-Chloro-2-(2-chloro-4-iodo-phenylamino)-benzoic acid 232-233
26 2-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzoic acid 179-182
27 4-Fluoro2-(2,3-dimethyl-4-iodo-2-methyl- 258-261 phenylamino)benzoic acid
28 5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic 209.5-211 acid
29 2-Chloro-6-(4-iodo-2-methyl-phenylamino)-benzoic acid 171-175
30 2-(4-Iodo-2-methyl-phenylamino)-4-nitro-benzoic acid 251-263
EXAMPLE 31 5-Chloro-N-(2-hvdroxyethyl)-2-(4-iodo-2-methyl-phenylamino -benzamide
To a stirring solution comprised of 0.1020 g (0.2632 mmol) of 5-chloro- 2-(4-iodo-2-methyl-phenylamino)-benzoic acid, 0.1 mL (1.7 mmol) of ethanolamine, and 0.05 mL (0.29 mmol) of diisopropylethylamine in 5 mL of a 1:1 (v/v) tetrahydrofuran-dichloromethane solution was added 0.15 g (0.29 mmol) of solid PyBOP powder directly. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The crude residue was partitioned between ether (50 mL) and 10% aqueous hydrochloric acid (50 mL). The organic phase was washed with 10% aqueous sodium hydroxide (50 mL), dried (MgSO-i) 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; iH NMR (400 MHz; CDCI3): δ 9.11 (s, IH), 7.56 (d, IH, J = 1.4 Hz), 7.46-7.41
(m, 2H), 7.20 (dd, IH, J = 8.9, 2.4 Hz), 7.00 (t, 2H, J = 9.6 Hz), 6.55 (broad t, IH), 3.86 (t, 2H, J = 5.0 Hz), 3.61 (dd, 2H, J = 10.1, 5.5 Hz), 2.23 (s, 3H), 1.56 (broad s, IH); IR (KBr) 3297 (O-H stretch), 1627 (C = O stretch) cm" 1 ;
MS (CI) M+1 = 431. Analysis calculated for C16Η16CIIN2O2:
C, 44.62; H, 3.74; N, 6.50. Found: 44.63; H, 3.67; N, 6.30.
EXAMPLES 32-48
By following the general procedure of Example 31, the following benzamides were prepared by reacting the corresponding benzoic acid with the corresponding amine.
Example Compound MP °C
No.
32 4-Methoxy-N-(4-methoxy-phenyl)-3-nitro- 153.5-156 benzamide
33 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 158 benzamide
34 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 102.5-104.5 methyl-benzamide
35 N-Ethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)- 90-91 benzamide
36 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N- oil dimethyl-benzamide
37 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(lH- 285-288 DEC tetrazol-5-yl)-benzamide
38 5-Bromo-2-(4-iodo-2-methyl-phenylamino)- 180-182 benzamide
39 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N- 137-138 dimethyl-benzamide Example Compound MP °C
No.
40 [5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 170-173 benzoylamino]-acetic acid
41 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 69-71 propyl-benzamide
42 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 132-133.4 phenylamino)-benzamide
43 N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl- oil phenylamino)-benzamide
44 4-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-yl]- 122-124 propyl } -2-(4-iodo-2-methyl-phenylamino)- benzamide
45 N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-5- 91-93 nitro-benzamide
46 N-Butyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)- 97-99 benzamide
47 5-Chloro-N,N-diethyl-2-(4-iodo-2-methyl- 118-120 phenylamino)-benzamide
48 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N,N- 142.5-144 dimethyl-benzamide
EXAMPLE 49 4-Fluoro-2-(4-iodo-2-methyl-phenylamino')-benzyl alcohol
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (0.50 g, 1.35 mmol) was dissolved in 6 mL (6 mmol) of cold 1.0 M borane- tetrahydrofuran complex in tetrahydrofuran solution. The reaction mixture was stirred under nitrogen atmosphere at room temperature overnight. The reaction was quenched with 80 mL of methanol. Concentration in vacuo produced a clear tan oil which was purified by MPLC. Elution with dichloromethane afforded 0.4285 g (89%) of a white solid; mp 99-100.5°C; iH NMR (400 MHz; DMSO): δ 7.57 (d, IH, J=1.7 Hz), 7.45 (dd, IH, J=8.4,
1.9 Hz), 7.39 (s, IH), 7.29 (t, IH, J=7.5 Hz), 6.89 (d, IH, J=8.4 Hz), 6.67-6.60 (m, IH), 5.47 (t, IH, J=5.5 Hz), 4.49 (d, 2H, 5.1 Hz), 2.14 (s, 3H); IR (KBr) 3372 (O-H stretch) cm"1;
MS (CI) M+l = 358.
Analysis calculated for C14H13FLNO:
C, 47.08; H, 3.67; N, 3.92. Found: C, 47.17; H, 3.75; N, 3.72.
EXAMPLE 50-52 The following benzyl alcohols were prepared by the general procedure of Example 49.
Example No. Compound MP °C
50 [5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 82-85 phenyl] -methanol
51 [2-(4-Iodo-2-methyl-phenylamino)-5-nitro-phenyl]- 126.5-128.5 methanol
52 [5-Bromo-2-(4-iodo-2-methyl-phenylamino)- 60.5-63.5 phenylj-methanol
Several invention compounds of Formula I were prepared utilizing combinatorial synthetic techniques. The general procedure is as follows:
To a 0.8-mL autosampler vial in a metal block was added 40 μL of a 0.5 M solution of the acid in DMF and 40 μL of the reagent amine (2 M solution in Hunig's base and 1 M in amine in DMF). A 0.5 M solution of PyBrop was freshly prepared and 50 μL were added to the autosampler vial. The reaction was allowed to stand for 24 hours.
The reaction mixture was transferred to a 2-dram vial and diluted with 2 mL of ethyl acetate. The organic layer was washed with 3 mL of distilled water and the water layer washed again with 2 mL of ethyl acetate. The combined organic layers were allowed to evaporate to dryness in an open fume hood. The residue was taken up in 2 mL of 50% acetonitrile in water and injected on a semi-prep reversed phase column (10 mm x 25 cm, 5 μM spherical silica, pore size 115 A derivatized with C-18, the sample was eluted at 4.7 mL/min with a linear ramp to 100% acetonitrile over 8.5 minutes. Elution with 100% acetonitrile continued for 8 minutes). Fractions were collected by monitoring at 214 nM. The residue was dissolved in chloroform and transferred to a preweighed vial, evaporated, and weighed again to determine the yield.
EXAMPLES 53-206 The following compounds of Formula I were prepared by combinatorial methodology:
Example Compound MS
No. M-H
53 5-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 510 phenylamino)-benzamide
54 N-(2,3-Dihydroxy-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- 462 phenylamino)-benzamide
55 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2- 577 piperidin- 1 -yl-ethyl)-benzamide
56 3,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 432 phenylamino)-benzamide
57 N-(2,3-Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl- 444 phenylamino)-benzamide
58 3,4-Difluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 446 phenylamino)-benzamide
59 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 564 (2-pyrrolidin- 1 -yl-ethyl)-benzamide
60 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 571 (2-pyridin-4-yl-ethyl)-benzamide
61 4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 414 benzamide 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-Benzyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 460
69 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-N-(2-hydroxy- 384 ethyl)-benzamide
70 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-mo holin-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 Example Compound MS
No. M-H
79 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- 461 benzamide
80 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- 475 ethyl)-benzamide
81 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyridin- 445 4-yl-ethyl)-benzamide
82 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(3-hydroxy- 400 propyl)-benzamide
83 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyrrolidin- 437 1 -yl-ethyl)-benzamide
84 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyl- 474 benzamide
85 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-thiophen- 450 2-yl-ethyl)-benzamide
86 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-pyridin- 431 4-ylmethyl-benzamide
87 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-N-phenethyl- 444 benzamide
88 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-piperidin- 451 l-yl-ethyl)-benzamide
89 5-Chloro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l -yl]-ρropyl}- 557* 2-(4-iodo-2-methyl- phenylamino)- benzamide
90 5-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-propyl}- 541* 2-(4-iodo-2-methyl- phenylamino)- benzamide
91 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl methyl- 487 benzamide
92 5-Bromo-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-propyl}- 601* 2-(4-iodo-2-methyl- phenylamino)- benzamide
93 5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- 486* phenylamino)- benzamide Example Compound MS
No. M-H
94 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-l-yl- 497* ethyl)-benzamide
95 (3-Hydroxy-pyrrolidin-l -yl)-[2-(4-iodo-2-methyl-phenylamino)- 466 5-nitro-phenyl]-methanone
96 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-l-yl- 484* ethyl)-benzamide
97 5-Bromo-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- 530* phenylamino)- benzamide
98 N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-chloro-2-(4-iodo- 518* 2-methyl- phenylamino)- benzamide
99 N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-bromo-2-(4-iodo- 562* 2-methyl- phenylamino)- benzamide
100 [5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(3-hydroxy- 499 pyrrolidin- 1 -yl)-methanone
101 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic acid phenethyl 501 ester
102 N- {3-[4-(2-Hydroxy-ethyl)-piperazin- 1 -yl]-propyl } -2-(4-iodo- 568 * 2-methyl-phenylamino)- benzamide
103 [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(3-hydroxy- 455 pyrrolidin- 1 -yl)-methanone
104 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- 460 benzamide
105 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-l-yl- 528* ethyl)-benzamide
106 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-l-yl- 542* ethyl)-benzamide
107 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2 -pyrrolidin- 1 -yl- 468* ethyl)-benzamide
108 5-Chloro-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- 472* phenylamino)-benzamide
109 N- {2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl } -5-fluoro-2-(4-iodo- 502* 2-methyl- phenylamino)- benzamide Example Compound MS
No. M-H
110 5-Chloro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 445* phenylamino)-benzamide
111 5-Chloro-N-(3 -diethylamino-2-hydroxy-propyl)-2-(4-iodo- 516* 2-methyl-phenylamino)- benzamide
112 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-l-yl- 482* ethyl)-benzamide
113 5-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 489* phenylamino)-benzamide
114 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl- 556* propyl)-benzamide
115 N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-2-(4-iodo-2-methyl- 529* phenylamino)-5 -nitro- benzamide
116 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- 500* ethyl)-benzamide
117 5-Chloro-N-(3-diethylamino-propyl)-2-(4-iodo-2-methyl- 500* phenylamino)-benzamide
118 5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- 514* phenylamino)-benzamide
119 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl- 512* propyl)-benzamide
120 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin- 1 -yl- 509* ethyl)-benzamide
121 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin-l-yl- 544* ethyl)-benzamide
122 N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl- 470* phenylamino)-benzamide
123 5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- 516* phenylamino)-benzamide
124 N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-5 -nitro- 456* benzamide Example Compound MS
No. M-H
125 5-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 429* phenylamino)-benzamide
126 N-(3-Diethylamino-propyl)-5-fluoro-2-(4-iodo-2-methyl- 484* phenylamino)-benzamide
127 N-(3 -Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- 511 * 5-nitro-benzamide
128 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- 544* ethyl)-benzamide
129 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin- 1 -yl- 523 * propyl)-benzamide
130 [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(3-hydroxy- 439 pyrrolidin- 1 -yl)-methanone
131 5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- 558* phenylamino)-benzamide
132 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- 484* ethyl)-benzamide
133 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl- 496* propyl)-benzamide
134 [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- 482 [4-(2-hydroxy-ethyl)-piperazin- 1 -yl]-methanone
135 N-(3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo- 500* 2-methyl-phenylamino)-benzamide
136 [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoylamino]- 443 acetic acid
137 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2-pyrrolidin- 1 -yl- 495 * ethyl)-benzamide
138 N-(3-Dimethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- 483* 5-nitro-benzamide
139 N-(2-Diisopropylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl- 498* phenylamino)- benzamide
140 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid S- 490 phenethyl ester Example Compound MS
No. M-H
141 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid S- 506 phenethyl ester
142 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid S- 536 benzyl ester
143 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-thiobenzoic acid S- 503 benzyl ester
144 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid S- 476 benzyl ester
145 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid S- 492 benzyl ester
146 N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 409 benzamide
147 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 429 benzamide
148 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 413 benzamide
149 N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 475 benzamide
150 N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- 593* benzamide
151 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl- 567 benzyl)-benzamide
152 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 473 benzamide
153 N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 521 benzamide
Example Compound MS
No. M-H
154 N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 440 benzamide
155 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- 486 benzamide
156 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- 425 benzamide
157 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 459 benzamide
158 N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 409
159 N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 583 benzamide
160 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- 538 benzyl)-benzamide
161 N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide 425
162 N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 436 benzamide
163 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- 469 benzamide
164 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 475 benzamide
165 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- 646 benzamide
166 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- 598 benzyl)-benzamide
167 N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 436
Example Compound MS
No. M-H
168 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl- 565 benzyl)-benzamide
169 N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide 469
170 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- 473 benzamide
171 N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 517 benzamide
172 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 519 benzamide
173 N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 502 benzamide
174 N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 559 benzamide
175 N-Allyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 517
176 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- 581 benzamide
177 2-(4-Iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-5-nitro- 500 benzamide
178 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 567 benzamide
179 N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 451 benzamide
180 5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- 467 benzamide
181 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- 533 benzamide
182 5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- 511 benzamide
183 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- 489 benzamide Example Compound MS
No. M-H
184 N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 478 benzamide
185 N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- 538 benzamine
186 N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 477 benzamide
187 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 431 benzamide
188 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 475 benzamide
189 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- 488 benzamide
190 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 477 benzamide
191 N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 523 benzamide
192 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- 425 benzamide
193 N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide 427
194 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 461 benzamide
195 N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 442 benzamide
196 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 415 benzamide
197 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- 472 benzamide
198 N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 411 benzamide
199 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- 540 benzyl)-benzamide Example Compound MS
No. M-H
200 N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 438 benzamide
201 N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 411
202 N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 585 benzamide
203 N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide 472
204 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- 601 benzyl)-benzamide
205 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 522 benzamide
206 N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 438
EXAMPLE 207 Preparation of [4-Chloro-2-(lH-tetrazol-5-yl -(4-iodo-2-methyl-phenyl)-amine
Step a: Preparation of 5-chloro-2-fluoro-benzaldehvde
To a solution of l-chloro-4-fluorobenzne (13.06 g, 0.1 mol) in THF (180 mL), at -78°C, LDA (2M solution in THF, 50 mL, 0.1 mol) was added drop wise. After stirring at -78°C for 1.5 hours, DMF (8 mL) was added to the reaction mixture and allowed to warm up to room temperature overnight. The reaction mixture was partitioned between water and Et2θ. The Et2θ layer was dried
(MgSO4) and the solvent removed in vacuum to give 14.95 g (94%) yield of crude aldehyde: 1H NMR (CDCI3): δ, 10.3 (s, -C(=O)H).
Step b: Preparation of 5-chloro-2-fluoro-benzaldehvde oxime
A solution of 5-chloro-2-fluoro-benzaldehyde (10 g, 0.0631 mol), hydroxylamine hydrochloride (6.57 g, 0.0946 mol) and pyridine (8.3 mL, 0.1010 mol) in EtOH (100 mL) was heated at 75°C (oil bath temperature) for 1 hour and the solvent removed under vacuum to give an oil. The oil was partitioned between water and CH2CI2. The CH2CI2 layer was dried (MgSO4) and the solvent removed under vacuum to give crude aldoxime as a solid. The solid was purified by medium pressure liquid chromatography on silica. Elution with CH2CI2 gave 4.87 g (28%) of the aldoxime as white solid: mp 95-97°C; Analysis calculated for C7H5NOFCI:
C, 48.44; H, 2.90; N, 8.07. Found: C, 48.55; H, 2.69, N, 7.90.
Step c: Preparation of 5-chloro-2-fluoro-benzonirile
A solution of the 5-chloro-2-fluoro-benzaldehyde oxime (3.15 g, 0.0182 mol) in acetic anhydride (150 mL) was refluxed for 16 hours. The reaction mixture was cooled to room temperature and poured into saturated aqueous NaHCO3 (200 mL) solution. The mixture was extracted with Et2θ. The E12O layer was dried (K2CO3) and the solvent removed to give the product as an oily solid. The product was used without further purification in the next step.
Step d: Preparation of 5-(5-chloro-2-fluoro-phenvD-lH-tetrazole
A mixture of 5-chloro-2-fluoro-benzonitrile (2.84 g, 0.01823 mol), butanol (15 mL), sodium azide (1.543 g, 0.0237 mol), acetic acid (1.36 mL, 0.0237 mol) was refluxed for 24 hours. The reaction mixture was cooled to room temperature, additional 1.543 g sodium azide added, and the reaction mixture refluxed for additional 24 hours. After cooling to room temperature, Et2θ (100 mL) and 10% aqueous NaOH (200 mL) were added sequentially. The mixture was vigorously stirred. The aqueous layer was separated, cooled with ice-methanol bath (-15°C) and acidified to pH 1 with cone. HC1. A gray solid precipitated. The solid was dried in vacuum at 50°C to give 1.76 g (49%) of 5-(5-chloro-2-fluoro-phenyl)-lH- tetrazole: mp partial melt at 110°C, complete melting at 124°C);
!H (400 Mz, CDCI3): δ 8.19-8.08 (m, IH), 7.77-7.71 (m, IH), 7.61-7.52 (m, IH);
13C (100 Mz, CDCI3): δ 159.00, 156.49, 140.88, 133.02, 132.93, 130.73, 129.23,
129.21, 129.08, 126.05, 118.96, 118.73, 114.50; MS (CI) M+l = 199 (100), M = 198 (6). Step e: Preparation of f 4-Chloro-2-( 1 H-tetrazol-5-ylW4-iodo-2-methyl-phenyl - amine
To a solution of 2-methyl-4-iodoaniline (3.52 g, 0.0151 mol) in THF (25 mL) at -78°C, LDA (2 molar solution in THF, 11.33 mL, 0.02267 mol) was added dropwise. After stirring for 0.5 hours, a solution of l-(tetrazol-5-yl)-2- fluoro-5-chlorobenzene (1.5 g, 0.00756 mol) in THF (15 mL) was added dropwise. The reaction was stirred for 16 hours as it warmed up to room temperature. The reaction mixture was quenched with aqueous cone. NH4CI solution and extracted with CH2CI2. The organic layer was dried (MgSO4) and the solvent removed giving a crude product as an oil. The oil with CH2CI2-
>CH2Cl2:MeOH (9.7:0.3) gave 1.5 g (48%) of the desired product: mp 205-208°C; H (400 Mz, DMSO): δ 9.13 (s, IH), 8.00-7.99 (s, IH), 7.69 (s, IH), 7.55-7.52 (m, IH), 7.43-7.40 (m, IH), 7.12-7.05 (m, IH), 2.24 (s, 3H); 13C (100 Mz, CDCI3): δ 141.87, 139.28, 138.88, 135.47, 133.71, 131.65, 128.15, 123.69, 121.94, 116.68, 87.79, 17.22; MS (CI) M+2 = 413 (44), M+1 = 412 (85),
M = 411 (100).
Analysis calculated for C 4H1 N5CII O.5H2O:
C, 39.97; H, 2.87; N, 16.65. Found: C, 38.87, H, 2.77; N, 16.47.
The following tetrazole substituted phenylamines were prepared by following the general procedure of Example 207.
EXAMPLE 208 (4-iodo-2-methyl-phenyl -[2-(lH-tetrazol-5-yl -phenyl]amine. mp 231°C (dec)
EXAMPLE 209 r4-nitro-2-(lH-tetrazol-5-yl -('4-iodo-2-methyl-phenylVamine. mp 205-208°C.
The 4-bromo and 4-iodo phenylamino benzhydroxamic acid derivatives of Formula II can be prepared from commercially available starting materials utilizing synthetic methodologies well-known to those skilled in organic chemistry. A typical synthesis is carried out by reacting a 4-bromo or 4-iodo aniline with a benzoic acid having a leaving group at the 2-position to give a phenylamino benzoic acid, and then reacting the benzoic acid phenylamino derivative with a hydroxylamine derivative (Scheme 3), where L is a leaving group, for example halo such as fluoro, chloro, bromo or iodo, or an activated hydroxy group such as a diethylphosphate, trimethylsilyloxy, p-nitrophenoxy, or phenylsulfonoxy.
The reaction of aniline and the benzoic acid derivative generally is accomplished by mixing the benzoic acid with an equimolar quantity or excess of the aniline in an unreactive organic solvent such as tetrahydrofuran, or toluene, in the presence of a base such as lithium diisopropylamide, n-butyl lithium, sodium hydride, and sodium amide. The reaction generally is carried out at a temperature of about -78°C to about 25°C, and normally is complete within about 2 hours to about 4 days. The product can be isolated by removing the solvent, for example by evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
Scheme 3
base
R6a HN-O- R 7a
The phenylamino benzoic acid next is reacted with a hydroxylamine derivative HNRgaOR7a in the presence of a peptide coupling reagent.
Hydroxylamine derivatives that can be employed include methoxylamine, N-ethyl-isopropoxy amine, and tetrahydro-oxazine. Typical coupling reagents include 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline (EEDQ), 1 ,3-dicyclohexylcarbodiimide (DCC), bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP) and (benzotriazolyloxy)tripyrrolidino phosphonium hexafluorophosphate (PyBOP). The phenylamino benzoic acid and hydroxylamino derivative normally are mixed in approximately equimolar quantities in an unreactive organic solvent such as dichloromethane, tetrahydrofuran, chloroform, or xylene, and an equimolar quantity of the coupling reagent is added. A base such as triethylamine or diisopropylethylamine can be added to act as an acid scavenger if desired. The coupling reaction generally is complete after about 10 minutes to 2 hours, and the product is readily isolated by removing the reaction solvent, for instance by evaporation under reduced pressure, and purifying the product by standard methods such as chromatography or crystallizations from solvents such as acetone, diethyl ether, or ethanol.
An alternative method for making the invention compounds involves first converting a benzoic acid to a hydroxamic acid derivative, and then reacting the hydroxamic acid derivative with an aniline. This synthetic sequence is depicted in Scheme 4, where L is a leaving group. The general reaction conditions for both of the steps in Scheme 4 are the same as those described above for Scheme 3.
Scheme 4
Yet another method for making invention compounds comprises reacting a phenylamino benzhydroxamic acid with an ester forming group as depicted in Scheme 5, where L is a leaving group such as halo, and a base is triethylamine or diisopropylamine.
Scheme 5
base
The synthesis of compounds of Formula (II) is further illustrated by the following detailed examples.
EXAMPLE la
4-Fluoro-N-hvdroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide
(a) Preparation of 4-Fluoro-2-(4-iodo-2-methyl-phenylamino -benzoic acid
To a stirred solution containing 3.16 g (0.0133 mol) of 2-amino- 5-iodotoluene in 5 mL of tetrahydrofuran at -78°C was added 10 mL (0.020 mol) of a 2.0 M lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene
(Aldrich) solution. The resulting green suspension was stirred vigorously for 15 minutes, after which time a solution of 1.00 g (0.00632 mol) of 2,4-difluorobenzoic acid in 10 mL of tetrahydrofuran was added. The reaction temperature was allowed to increase slowly to room temperature, at which temperature the mixture was stirred for 2 days. The reaction mixture was concentrated by evaporation of the solvent under reduced pressure. Aqueous HCl (10%o) was added to the concentrate, and the solution was extracted with dichloromethane. The organic phase was dried (MgSO4) and then concentrated over a steambath to low volume (10 mL) and cooled to room temperature. The off-white fibers which formed were collected by vacuum filtration, rinsed with hexane, and dried in a vacuum-oven (76°C; ca. 10 mm of Hg) to afford 1.10 g
(47%>) of the desired material; mp 224-229.5°C;
*H NMR (400 MHz, DMSO): δ 9.72 (s, IH), 7.97 (dd, IH, J=7.0, 8.7 Hz), 7.70 (d, IH, J=1.5 Hz), 7.57 (dd, IH, J=8.4, 1.9 Hz), 7.17 (d, IH, J=8.2 Hz), 6.61-6.53 (m, 2H), 2.18 (s, 3H); 13C NMR (100 MHz, DMSO): δ 169.87, 166.36 (d, JC-F=249.4 Hz), 150.11 (d,
JC.F=11.4 Hz), 139.83, 138.49, 136.07, 135.26 (d, Jc-F=1 1-5 Hz)> 135.07, 125.60, 109.32, 104.98 (d, Jc-F=21.1 Hz), 99.54 (d, JC-F=26.0 Hz), 89.43, 17.52; 19F NMR (376 MHz, DMSO): δ -104.00 to -104.07 (m);
IR (KBr) 1670 (C=O stretch)cm"l; MS (CI) M+1 = 372.
Analysis calculated for C14H11FINO2:
C, 45.31; H, 2.99; N, 3.77. Found: C, 45.21; H, 2.77; N, 3.64.
(b) Preparation of 4-Fluoro-N-hvdroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide
To a stirred solution of 4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (0.6495 g, 0.001750 mol), O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (0.2590 g, 0.002211 mol), and diisopropylethylamine (0.40 mL, 0.0023 mol) in 31 mL of an equivolume tetrahydrofuran-dichloromethane solution was added 1.18 g (0.00227 mol) of solid PyBOP ([benzotriazolyloxyjtripyrrolidino phosphonium hexafluorophosphate, Advanced ChemTech) directly. The reaction mixture was stirred for 30 minutes after which time it was concentrated in vacuo. The brown oil was treated with 10% aqueous hydrochloric acid. The suspension was extracted with ether. The organic extraction was washed with 10% sodium hydroxide followed by another 10% hydrochloric acid wash, was dried (MgSO4) and concentrated in vacuo to afford 1.0 g of a light-brown foam. This intermediate was dissolved in 25 mL of ethanolic hydrogen chloride, and the solution was allowed to stand at room temperature for 15 minutes. The reaction mixture was concentrated in vacuo to a brown oil that was purified by flash silica chromatography. Elution with a gradient (100 % dichloromethane to 0.6 % methanol in dichloromethane) afforded 0.2284 g of a light-brown viscous oil. Scratching with pentane-hexanes and drying under high vacuum afforded 0.1541 g (23%) of an off-white foam; mp 61-75°C; iH NMR (400 MHz, DMSO): δ 11.34 (s, IH), 9.68 (s, IH), 9.18 (s, IH), 7.65 (d, IH, J=1.5 Hz), 7.58 (dd, IH, J=8.7, 6.8 Hz), 7.52 (dd, IH, J=8.4, 1.9 Hz), 7.15 (d,
IH, J=8.4 Hz), 6.74 (dd, IH, J=l 1.8, 2.4 Hz), 6.62 (ddd, IH, J=8.4, 8.4, 2.7 Hz),
2.18 (s, 3H);
13C NMR (100 MHz, DMSO): δ 165.91, 164.36 (d, Jc-F=247.1 Hz), 146.78,
139.18, 138.77, 135.43, 132.64, 130.60 (d, Jc-F^H-5 Hz), 122.23, 112.52, 104.72 (d, J=22.1 Hz), 100.45 (d, JC-F=25.2 Hz), 86.77, 17.03;
19F NMR (376 MHz, DMSO): δ -107.20 to -107.27 (m);
IR (KBr) 3307 (broad, O-H stretch), 1636 (C=O stretch) cm"1; MS (CI) M+1 = 387. Analysis calculated for C14H 2FIN2O2: C, 43.54; H, 3.13; N, 7.25.
Found: C, 43.62; H, 3.24; N, 6.98.
EXAMPLE 2a 5-Bromo-3.4-difluoro-N-hvdroχy-2-(4-iodo-2-methyl-phenylamino)-benzamide (a) Preparation of 5-Bromo-2.3.4-trifluorobenzoic acid To a stirred solution comprised of l-bromo-2,3,4-trifluorobenzene
(Aldrich, 99%; 5.30 g, 0.0249 mol) in 95 mL of anhydrous tetrahydrofuran cooled to -78°C was slowly added 12.5 mL of 2.0 M lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene solution (Aldrich). The mixture was stirred for 1 hour and transferred by canula into 700 mL of a stirred saturated ethereal carbon dioxide solution cooled to -78°C. The cold bath was removed, and the reaction mixture was stirred for 18 hours at ambient temperature. Dilute (10%) aqueous hydrochloric acid (ca. 500 mL) was poured into the reaction mixture, and the mixture was subsequently concentrated on a rotary evaporator to a crude solid. The solid product was partitioned between diethyl ether (150 mL) and aq. HCl (330 mL, pH 0). The aqueous phase was extracted with a second portion (100 mL) of diethyl ether, and the combined ethereal extracts were washed with 5% aqueous sodium hydroxide (200 mL) and water (100 mL, pH 12). These combined alkaline aqueous extractions were acidified to pH 0 with concentrated aqueous hydrochloric acid. The resulting suspension was extracted with ether (2 x 200 mL). The combined organic extracts were dried (MgSO4), concentrated in vacuo, and subjected to high vacuum until constant mass was achieved to afford 5.60 g (88% yield) of an off-white powder; mp 139-142.5°C; iH NMR (400 MHz, DMSO): δ 13.97 (broad s, IH, 8.00-7.96 (m, IH);
13c NMR (100 MHz, DMSO): δ 162.96, 129.34, 118.47, 104.54 (d, J -F=22.9 Hz);
19F NMR (376 MHz, DMSO): δ -120.20 to -120.31 (m), -131.75 to -131.86 (m), -154.95 to -155.07 (m);
IR (KBr) 1696 (C=O stretch)cm-l; MS (CI) M+1 = 255. Analysis calculated for C74H21 BrF3 O2 :
C, 32.97; H, 0.79; N, 0.00; Br, 31.34; F, 22.35. Found: C, 33.18; H, 0.64; N, 0.01; Br, 30.14; F, 22.75.
(b) Preparation of 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino - benzoic acid To a stirred solution comprised of 1.88 g (0.00791 mol) of 2-amino-
5-iodotoluene in 10 mL of tetrahydrofuran at -78°C was added 6 mL (0.012 mol) of a 2.0 M lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (Aldrich) solution. The resulting green suspension was stirred vigorously for 10 minutes, after which time a solution of 1.00 g (0.00392 mol) of 5-bromo- 2,3,4-trifluorobenzoic acid in 15 mL of tetrahydrofuran was added. The cold bath was subsequently removed, and the reaction mixture stirred for 18 hours. The mixture was concentrated, and the concentrate was treated with 100 mL of dilute (10%) aqueous hydrochloric acid. The resulting suspension was extracted with ether (2 x 150 mL), and the combined organic extractions were dried (MgSO4) and concentrated in vacuo to give an orange solid. The solid was triturated with boiling dichloromethane, cooled to ambient temperature, and collected by filtration. The solid was rinsed with dichloromethane, and dried in the vacuum- oven (80°C) to afford 1.39 g (76%) of a yellow-green powder; mp 259.5-262°C; iH NMR (400 MHz, DMSO): δ 9.03 (s, IH), 7.99 (dd, IH, J=7.5, 1.9 Hz), 7.57 (dd, IH, J=1.5 Hz), 7.42 (dd, IH, J=8.4, 1.9 Hz), 6.70 (dd, IH, J=8.4,
6.0 Hz), 2.24 (s, 3H);
19F NMR (376 MHz, DMSO): δ -123.40 to -123.47 (m); -139.00 to -139.14 (m);
IR (KBr) 1667 (CO stretch)cm"l; MS (CI) M+1 = 469. Analysis calculated for C 14H9BrF2lNO2 :
C, 35.93; H, 1.94; N, 2.99; Br, 17.07; F, 8.12; 1, 27.11. Found: C, 36.15; H, 1.91; N, 2.70; Br, 16.40; F, 8.46; 1, 26.05. (c) Preparation of 5-Bromo-3.4-difluoro-N-hvdroxy-2-(4-iodo-2-methyl- phenylaminoVbenzamide To a stirred solution comprised of 5-bromo-3,4-difluoro-2-(4-iodo-
2-methyl-phenylamino)-benzoic acid (0.51 g, 0.0011 mol), O-(tetrahydro-2H- pyran-2-yl)-hydroxylamine (0.15 g, 0.0013 mol), and diisopropylethylamine (0.25 mL, 0.0014 mol) in 20 mL of an equivolume tetrahydrofuran- dichloromethane solution was added 0.6794 g (0.001306 mol) of solid PyBOP (Advanced ChemTech) directly. The reaction mixture was stirred at 24°C for
10 minutes, and then was concentrated to dryness in vacuo. The concentrate was suspended in 100 mL of 10% aqueous hydrochloric acid. The suspension was extracted with 125 mL of diethyl ether. The ether layer was separated, washed with 75 mL of 10% aqueous sodium hydroxide, and then with 100 mL of dilute acid. The ether solution was dried (MgSO4) and concentrated in vacuo to afford
0.62 g (100%) of an off-white foam. The foam was dissolved in ca. 15 mL of methanolic hydrogen chloride. After 5 minutes, the solution was concentrated in vacuo to an oil, and the oil was purified by flash silica chromatography. Elution with dichloromethane: dichloromethane-methanol (99:1) afforded 0.2233 g (42%) of a yellow powder. The powder was dissolved in diethyl ether and washed with dilute hydrochloric acid. The organic phase was dried (MgSO4) and concentrated in vacuo to afford 0.200 g of a foam. This product was triturated with pentane to afford 0.1525 g of a powder that was repurified by flash silica chromatography. Elution with dichloromethane afforded 0.0783 g (15%) of an analytically pure title compound, mp 80-90°C; iH NMR (400 MHz, DMSO): δ l 1.53 (s, IH), 9.38 (s, IH), 8.82 (s, lH), 7.70 (dd,
IH, J=7.0, 1.9 Hz), 7.53 (s, IH), 7.37 (dd, IH, J=8.4, 1.9 Hz), 6.55 (dd, IH, J=8.2, 6.5 Hz), 2.22 (s, 3H);
! 9F NMR (376 MHz, DMSO): δ -126.24 to -126.29 (m), -137.71 to -137.77 (m);
IR (KBr) 3346 (broad, O-H stretch), 1651 (C=O stretch)cm"l; MS (CI) M+1 = 484.
Analysis calculated for Ci4Hκ)BrF2lN2θ2:
C, 34.81; H, 2.09; N, 5.80. Found: C, 34.53; H, 1.73; N, 5.52.
Examples 3 a to 12a in the table below were prepared by the general procedure of Examples la and 2a.
EXAMPLES 13a-77a Examples 13a to 77a were prepared utilizing combinatorial synthetic methodology by reacting appropriately substituted phenylamino benzoic acids
(e.g., as shown in Scheme 1) and hydroxylamines (e.g., (NHR^a )-O-R7a). A general method is given below:
To a 0.8-mL autosampler vial in a metal block was added 40 μL of a 0.5 M solution of the acid in DMF and 40 μL of the hydroxylamine (2 M solution in Hunig's base and 1 M in amine in DMF). A 0.5 M solution of PyBrOP was freshly prepared, and 50 μL were added to the autosampler vial. The reaction was allowed to stand for 24 hours.
The reaction mixture was transferred to a 2-dram vial and diluted with 2 mL of ethyl acetate. The organic layer was washed with 3 mL of distilled water and the water layer washed again with 2 mL of ethyl acetate. The combined organic layers were allowed to evaporate to dryness in an open fume hood.
The residue was taken up in 2 mL of 50% acetonitrile in water and injected on a semi -prep reversed phase column (10 mm x 25 cm, 5 μM spherical silica, pore Size 115 A derivatized with C-18, the sample was eluted at 4.7 mL/min with a linear ramp to 100%) acetonitrile over 8.5 minutes. Elution with 100% acetonitrile continued for 8 minutes.) Fractions were collected by monitoring at 214 nM. The desired fractions were evaporated using a Zymark Turbovap. The product was dissolved in chloroform and transferred to a preweighed vial, evaporated, and weighed again to determine the yield. The structure was confirmed by mass spectroscopy.
EXAMPLES 3a-77a Example Compound Melting MS
No. Point (°C) (M-H+)
3a 2-(4-bromo-2-methyl-phenylamino)-4-fluoro-N- 56-75 dec 523 hydroxy-benzamide
4a 5-Chloro-N-hydroxy-2-(4-iodo-2-methyl- 65 dec phenylamino)-benzamide
5a 5-Chloro-N-hydroxy-2-(4-iodo-2-methyl- 62-67 phenylamino)-N-methyl-benzamide
6a 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N- 105-108 (terahydropyran-2-yloxy)benzamide
7a 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N- 64-68 methoxybenzamide
8a 4-Fluoro-N-hydroxy-2-(4-fluoro-2-methyl- 119-135 phenylamino)-benzamide
9a 4-Fluoro-N-hydroxy-2-(2-methyl phenylamino)- 101-103 benzamide
10a 4-Fluoro-2-(4-fluor-2-methyl-phenylamino)-N- 142-146 (terahydropyran-2-yloxy)benzamide
11a 4-Fluoro-N-hydroxy-2-(4-cluoro-2-methyl- 133.5-135 phenylamino)-benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
Ϊ2a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 107-109.5 phenylmethoxy-benzamide
13a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 399 methoxy-benzamide
14a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 417
N-methoxy-benzamide
15a 2-(4-Bromo-2-methyl-phenylamino)- 369
3 ,4-difluoro-N-methoxy-benzamide
16a 2-(4-Bromo-2-methyl-phenylamino)-N-ethoxy- 342*
3,4-difluoro-benzamide (M-EtO)
17a 5-Bromo-N-ethoxy-3,4-difluoro-2-(4-iodo- 509
2-methyl-phenylamino)-benzamide
18a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 445
N-isopropoxy-benzamide
19a 2-(4-Bromo-2-methyl-phenylamino)- 397
3,4-difluoro-N-isopropoxy-benzamide
20a 4-Fluoro-N-(furan-3-ylmethoxy)-2-(4-iodo- 465
2-methyl-phenylamino)-benzamide Example Compound Melting MS
No. Point (°C) (M-H+) 2Ϊa 3,4-Difluoro-N-(furan-3-ylmethoxy)-2-(4-iodo- 483
2-methyl-phenylamino)-benzamide
22a 2-(4-Bromo-2-methyl-phenylamino)- 435
3,4-difluoro-N-(furan-3-ylmethoxy)-benzamide
23a 5-Bromo-3,4-difluoro-N-(furan-3-ylmethoxy)- 561
2-(4-iodo-2-methyl-phenylamino)-benzamide
24a 5-Bromo-N-(but-2-enyloxy)-3,4-difluoro- 536
2-(4-iodo-2-methyl-phenylamino)-benzamide
25a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 423
(prop-2-ynyloxy)-benzamide
26a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 441
N-(prop-2-ynyloxy)-benzamide
27a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 455
N-( 1 -methyl-prop-2-ynyloxy)-benzamide
28a 2-(4-Bromo-2-methyl-phenylamino)- 407
3 ,4-difluoro-N-( 1 -methyl-prop-2-ynyloxy)- benzamide
29a N-(But-3-ynyloxy)-3,4-difluoro-2-(4-iodo- 455
2-methyl-phenylamino)-benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
30a 2-(4-Bromo-2-methyl-phenylamino)-N-(but- 407 3 -ynyloxy)-3 ,4-difluoro-benzamide
31a 5-Bromo-N-(but-3-ynyloxy)-3,4-difluoro- 533
2-(4-iodo-2-methyl-phenylamino)-benzamide
32a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 517
N-(3-phenyl-prop-2-ynyloxy)-benzamide
33a 3,4-Difluoro-2-(4-bromo-2-methyl- 469 phenylamino)-N-(3-phenyl-prop-2-ynyloxy)- benzamide
34a 3,4-Difluoro-N-[3-(3-fluoro-phenyl)-prop- 535
2-ynyloxy]-2-(4-iodo-2-methyl-phenylamino)- benzamide
35a 2-(4-Bromo-2-methyl-phenylamino)- 487
3 ,4-difluoro-N- [3 -(3 -fluoro-phenyl)-prop- 2-ynyloxy]-benzamide
36a 3,4-Difluoro-N-[3-(2-fluoro-phenyl)-prop- 535
2-ynyloxy]-2-(4-iodo-2-methyl-phenylamino)- benzamide
37a 5-Bromo-3,4-difluoro-N-[3-(2-fluoro-phenyl)- 613 prop-2-ynyloxy]-2-(4-iodo-2-methyl- phenylamino)-benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
38a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 557*
N-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)- *(M+H) benzamide
39a 2-(4-Bromo-2-methyl-phenylamino)- 510
3,4-difluoro-N-(3-methyl-5-phenyl-pent-2-en- 4-ynyloxy)-benzamide
40a N-Ethoxy-3,4-difluoro-2-(4-iodo-2-methyl- 431 phenylamino)-benzamide
41a 2-(4-Bromo-2-methyl-phenylamino)-N-ethoxy- 383
3 ,4-difluoro-benzamide
42a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 427 propoxy-benzamide
43 a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 445
N-propoxy-benzamide
44a 2-(4-Bromo-2-methyl-phenylamino)- 397
3 ,4-difluoro-N-propoxy-benzamide
45a 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 523 phenylamino)-N-propoxy-benzamide
46a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 427 isopropoxy-benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
47a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 445 N-isopropoxy-benzamide
48a 2-(4-Bromo-2-methyl-phenylamino)- 397
3,4-difluoro-N-isopropoxy-benzamide
49a 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 523 phenylamino)-N-isopropoxy-benzamide
50a N-Cyclobutyloxy-3,4-difluoro-2-(4-iodo- 457
2-methyl-phenylamino)-benzamide
51a 2-(4-Bromo-2-methyl-phenylamino)-N- 409 cyclobutyloxy-3,4-difluoro-benzamide
52a N-Cyclopentyloxy-4-fluoro-2-(4-iodo-2-methyl- 453 phenylamino)-benzamide
53a N-Cyclopentyloxy-3,4-difluoro-2-(4-iodo- 471
2-methyl-phenylamino)-benzamide
54a 2-(4-Bromo-2-methyl-phenylamino)-N- 423 cyclopentyloxy-3,4-difluoro-benzamide
55a N-Cyclopropylmethoxy-4-fluoro-2-(4-iodo- 439
2-methyl-phenylamino)-benzamide
56a N-Cyclopropylmethoxy-3,4-difluoro-2-(4-iodo- 457
2-methyl-phenylamino)-benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
57a 2-(4-Bromo-2-methyl-phenylamino)-N- 409 cyclopropylmethoxy-3,4-difluoro-benzamide
58a 5-Bromo-N-cyclopropylmethoxy-3,4-difluoro- 435
2-(4-iodo-2-methyl-phenylamino) 59a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 505
(2-phenoxy-ethoxy)-benzamide
60a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 523
N-(2-phenoxy-ethoxy)-benzamide
61a 2-(4-Bromo-2-methyl-phenylamino)- 475
3,4-difluoro-N-(2-phenoxy-ethoxy)-benzamide
62a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 481
(thiophen-2-ylmethoxy)-benzamide
63a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 499
N-(thiophen-2-ylmethoxy)-benzamide
64a 2-(4-Bromo-2-methyl-phenylamino)- 451
3,4-difluoro-N-(thiophen-2-ylmethoxy)- benzamide
65a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 439
(2-methyl-allyloxy)-benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
66a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 457 N-(2-methyl-allyloxy)-benzamide
67a 2-(4-Bromo-2-methyl-phenylamino)- 410
3,4-difluoro-N-(2-methyl-allyloxy)-benzamide
68a N-(But-2-enyloxy)-4-fluoro-2-(4-iodo-2-methyl- 439 phenylamino)-benzamide
69a N-(But-2-enyloxy)-3,4-difluoro-2-(4-iodo- 457
2-methyl-phenylamino)-benzamide
70a 2-(4-Bromo-2-methyl-phenylamino)-N-(but- 410
2-enyloxy)-3 ,4-difluoro-benzamide
71a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 441
N-(prop-2-ynyloxy)-benzamide
72a N-(But-3-ynyloxy)-3,4-difluoro-2-(4-iodo- 455
2-methyl-phenylamino)-benzamide
73a 2-(4-Bromo-2-methyl-phenylamino)-N- 449
(4,4-dimethyl-pent-2-ynyloxy)-3,4-difluoro- benzamide
74a N-(But-2-enyloxy)-3,4-difluoro-2-(4-iodo- 457
2-methyl-phenylamino)-benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
75a 2-(4-Bromo-2-methyl-phenylamino)-N-(but- 410 2-enyloxy)-3,4-difluoro-benzamide
76a N-(3-tert-butyl-propyn-2-yl)oxy-4-fluoro- 479 2-(4-iodo-2-methyl-phenylamino)-benzamide
77a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 577 phenylmethoxy-benzamide
PHYSICAL DATA FOR SELECTED COMPOUNDS
PD 0171984
mp 80-90 °C
PD 0184161
mp 174-175 °C
PD 0203311
mp 141-144 °C
PD 0297189
mp l67-169 °C
1H-NMR (400 MHz; DMSO) δ 11.70 (s, IH), 8.59 (s, IH), 7.55 (s, IH), 7.43 (d, IH, J=6.5 Hz), 7.27 (d,lH, J=8.7 Hz), 6.46 (m, IH), 3.42 (d, 2H, J=7.0 Hz), 0.84 (m, IH), 0.27 (m, 2H), 0.00 (m, 2H) PD 0297190 mp 125.5-133 °C
1H-NMR (400 MHz; DMSO) δ 11.48 (s, IH), 8.32 (s, IH), 7.34 (d, IH, J=7.5 Hz), 7.28 (d, 2H, J=8.2 Hz), 6.48 (d, 2H, J=7.7 Hz), 3.32 (d, 2H, J=6.8 Hz), 0.81 (m, IH), 0.28 (m, 2H), 0.00 (m, 2H)
PD 0296771
mp 266.7-268.9 °C
1H-NMR (400 MHz; DMSO) δ 13.85 (broad s, IH), 8.99 (s, IH), 7.87 (dd, IH, J=7.9, 2.1 Hz), 7.55 (d,2H, J=8.6 Hz), 6.82 (dd, 2H, J=8.7, 2.8 Hz)
PD 0296770
mp 293.2-296.3 °C
Η-NMR (400 MHz; DMSO) δ 14.05 (broad s, IH), 9.21 (s, IH), 7.93 (dd, IH, J=7.8, 2.2 Hz), 7.82 (d,lH, J=1.9 Hz), 7.54 (dd, IH, J=8.6, 1.9 Hz), 6.82 (dd, IH,
J=8.6, 6.7 Hz)
PD 0296767
mp 249-251 °C
1H-NMR (400 MHz; DMSO) δ 13.99 (broad s, IH), 9.01 (s, IH), 7.90 (dd, IH, J=7.9, 2.3 Hz), 7.58 (d,lH, J=1.6 Hz), 7.42 (dd, IH, J=8.4, 1.9 Hz), 6.69 (dd, IH, J=8.4, 6.0 Hz), 2.24 (s, 3H)
PD 298127
mp 127-135 °C
5-chloro-N-cyclopropyl methoxy-3,4-difluoro-2-[4-iodo-2 -methyl phenylamino]benzamide
1H NMR (440 MHz; DMSO) δ 11.64 (s, IH), 8.28 (s, IH), 7.38 (dd, IH, J=7.6, 1.7 Hz), 7.31 (d, 1 H, J=1.2 Hz), 7.15 (dd, IH, J=8.5, 1.7 Hz), 3.35 (d, 2H, J=7.3 Hz), 2.01 (s, 3H), 0.83 (m, IH), 0.28 (m,2H), 0.01 (m, 2H) BIOLOGICAL ASSAYS
The ability of selective MEK inhibitors to prevent and treat viral infections in mammals has been established in standard assays designed to measure antiviral utility. A typical screen to assess activity against herpesvirus (HSV) is called the
"ANUS" screen. This screen is designed to identify compounds which inhibit HSV-1 in phases of its life cycle from adsorption and penetration through late gene expression. The primary screen, ANUS1, involves adding single compounds to a monolayer of Vero cells to a final concentration of 25 μg/mL, then infecting the cells with a recombinant HSN-1, Us3::Tn5-lacZ. This virus contains an insertion of a lacZ gene driven by a viral late promoter in the US3 protein kinase gene of HSV-1. The infection is allowed to proceed for 20 hours, then the cells are lysed with a solution of Triton X-100 and CPRG in "Z" buffer and assayed for β-galactosidase activity. The positive control used is solvent alone without test compound, which corresponds to 0% inhibition, and the negative control used is either no virus added to the wells or 0.5% Triton X-100 added to the wells, which corresponds to 100% inhibition. Percent inhibition of viral growth is then calculated using the positive and the negative controls.
Test compounds which cause at least an 80% inhibition in the AVUS 1 assay are carried forward into a secondary screen, AVUS2, in which a titration of the compound from the frozen diluted stock of the AVUS1 screen is assayed for inhibition of HSV-1 via the same β-galactosidase and toxicity via a 1-day XTT assay in the absence of virus. Those compounds which have good activities (<2 μg/mL), good therapeutic indices (> 10-fold), and which are not planar compounds are then carried forward into a tertiary screen termed AVUS3.
In the AVUS3 assay, the test compound is dissolved in MeOH at 20 nM. A titration of the compound is then assayed in both the same β-galactosidase virus replication inhibition assay, and a 5-day XTT toxicity assay. Follow-up screens to this core set of AVUS screens include plaque reduction and yield reduction assays with wild-type HSV-1 to verify antiviral activity, and time course of addition studies to begin to dissect a possible mechanism of action. Several of the selective MEK inhibitors have been evaluated in assays to measure their ability to prevent and inhibit growth of human cytomegleovirus (HCMV) and herpesvirus (HSV-1). As discussed above, the toxicity of representative compounds has also been determined. Table 1 below presents the results of such assays for several of the compounds described above. In the Table, the antiviral activity is presented as IC50 (the concentration of test compound required to inhibit viral growth by 50%), and toxicity is reported as TC50 (the concentration of test compound which killed 50% of the cells).
Table 1 Selective MEK HCMV HSV-1
Inhibitor IC50 TC50 IC50 TC50
98059a 17 μM 50 μM >50 μM >50 μM
17061 lb 2.2 μM 30 μM 6.9 μM 13 μM
177168° 0.8 μM 9 μM 3.0 μM 11 μM
2-(2-amino-3-methoxyphenyl)-4-oxo-4H-[ 1 Jbenzopyran
2-(2-methyl-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide
2-(2-methyl-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro-
5-bromobenzamide
The selective MEK inhibitors have been evaluated in standard assays to determine their ability to prevent and treat HIV infections. One of the assays used to determine the activity against the HIV virus is that employed by the US national Cancer Institute as described by Weislow et al., J Natl. Cancer Inst., 1989; 81:577-586, incorporated herein by reference. Other assays commonly used include the MTT cell culture assays using CEM or MT2 cells. This assay involves the conversion of the tetrazolium dye MTT to a colored formazan product by mitochondrial enzymes in metabolically active cells. These assays are routinely used by Southern Research Institute (SRI) in an established program for determining primary antiviral activity of compounds. These tests are fully described in US 5,484,926, incorporated herein by reference. The Weislow et al procedure is described below. The procedure is designed to detect agents acting at any stage of the virus reproductive cycle. The assay basically involves the killing of T4 lymphocytes by HIV. Small amounts of HIV are added to cells, and at least two complete cycles of virus reproduction are necessary to obtain the required cell killing. Agents which interact with virions, cells, or virus gene-products to interfere with viral activities will protect cells from cytolysis. The system is automated in several features to accommodate large numbers of candidate agents, and is generally designed to detect anti-HIV activity. However, compounds which degenerate or are rapidly metabolized in the culture conditions may not show activity in this screen. Another test system utilized to evaluate the invention compounds is called
HIV H9 assay. The HIV H9 cell assay measures the inhibitor concentration required to suppress HIV-1 virus replication. In this system, viral growth occurs through multiple rounds of the life-cycle. Any suppression of the replication kinetics results in a geometric decrease in virus production. As a result, this assay is a sensitive means of measuring the ability of a compound to inhibit HIV-1 viral replication.
The H9 T-cell line is batch infected with HIV virus at an MOI of 0.01. After 2 hours absorption, the cells are washed, resuspended in RPMI- 1640/10% fetal calf serum, and seeded at 5 x 10-3 cells/well of a 96-well plate. A duplicate plate of uninfected H9 cells is prepared for the cytotoxicity assay. Drugs are serially diluted 1/3.16 in DMSO, transferred to media at a x8 concentration, and then added to the cultures in triplicate. The final DMSO concentration of 0.002 (0.2%).
Viral production is measured by RT assay and cytotoxicity is measured by XTT assay at 7 days post-infection. The RT assay is performed as a modification of Borroto-Esoda and Boone, J. Virol., 1991;65:1952-1959 and quantitated using a Molecular Dynamics Phosphoimager with Imagequant software. The XTT assay is performed as a modification of Roehm, et al., J. Immuno. Methods., 1991;142:257-265 and quantitated using a molecular Devices Thermomax plate reader with Softmax software.
Data is electronically transferred to a Microsoft Excell spreadsheet for analysis. The RT assay values equivalent to 50% and 90% inhibition of virus production are calculated from the untreated controls. The concentrations of inhibitor required to produce these values (IC50 and IC90) are interpolated from data points flanking these RT activities. The XTT assay values equivalent to 50% cytotoxicity are calculated from the untreated controls. The concentrations of inhibitor required to produce this value are interpolated from data points flanking these XTT values.
Yet another test system employed to determine antiviral activity is called the CEM cell assay.
T4 lymphocytes (CEM cell line) are exposed to HIV at a virus to cell ratio approximately 0.05, and plated along with noninfected control cells in 96-well microliter plates.
Candidate agent is dissolved in dimethyl sulfoxide (unless otherwise noted), then diluted 1 :200 in cell culture medium. Further dilutions (half-log 10) are prepared before adding to an equal volume of medium containing either infected or noninfected cells.
Cultures are incubated at 37° in a 5% carbon dioxide atmosphere for 6 or 7 days. The tetrazolium salt, XTT, is added to all wells, and cultures are incubated to allow formazan color development by viable cells J. National Cancer Institute, 1989;81 :577-586. Individual wells are analyzed spectrophotometrically to quantitate formazan production, and in addition are viewed microscopically for detection of viable cells confirmation of protective activity.
Drug-tested virus-infected cells are compared with drug-treated noninfected cells and with other appropriate controls (untreated infected and untreated noninfected cells, drug-contain wells without cells, etc.) on the same plate. Data are reviewed in comparison with other tests done at the same time and a determination about activity is made.
Table 2 below shows the anti-HIV activity of several selective MEK inhibitors. The Table presents EC50 ( CEMss-HIV 1 Rf) and TC 50 values. Table 2
FRC-26 EC50 TC50* TC50**
0177098 toxic > 6.25 μM 18.5 μM 7.9 μM
0184161 toxic > 6.25 μM 6.0 μM 8.5 μM
0185625 toxic > 6.25 μM 16.7 μM 10.1 μM
0185848-0002 toxic > 6.25 μM 18.3 μM 10.3 μM
0198306 toxic > 6.25 μM 16.7 μM 10.2 μM
0203311 toxic > 6.25 μM 19.5 μM 20 μM
0177168 0.18 μM*** 5.95 μM 4.9 μM
0180841 toxic > 6.25 μM 6.0 μM 6.1 μM
0170611 toxic > 6.25 μM 13.8 μM 7 μM
0098059 >200 μM >200 μM >100 μM
AZT 0.005 μM >1 μM
PD 178390 (PI control) 0.18 μM >100 μM
* By XTT
** Determined using the Amersham cytostar SPA assay for thymidine incorporation *** To be retested
Compound 177168 gave an excellent dose response with the rest being flat liners in regards to antiviral activity. Testing against Ba-L in macrophages is ongoing and data will be available in about 10 days.
Several of the selective MEK inhibitors were further evaluated against Ba-L in macrophages, and retested in CEM-XTT and macrophage XTT assays, as well as measuring HFF thymidine incorporation. The results are presented in below in Table 3. Table 3 Antiviral Activity of MEK Inhibitors
Compound MOL Structure HIV Rf/CEM HIV BaL/ TC50 CEM TC50 Macros TC50 HFF Macros XTT XTT Thym Incorp
EC50 μM EC50 μM μM μM μM
AZT 0.005 0.01 >1 >200
178390 0.18 1.3 >100 >4
177168 0.18* 3.51 3.3 >200 4.9
185848 toxic >6.25 0.3 5.5 161.7 10.3
185625 toxic >6.25 0.36 4.7 116.2 10.1
203311 toxic >6.25 0.55 7.8 >200 20
184161 toxic >6.25 0.79 3.7 47.5 8.5
180841 toxic >6.25 0.97 4 17.2 6.1
198306 toxic >6.25 5.5 4.6 191 10.2
170611 toxic >6.25 18.7 4 199 7
177098 toxic >6.25 22.9 5.8 187 7.9
98095 >200 >200 197 >200 >100
* To be retested
The foregoing data establish that MEK inhibitors are active in both preventing a viral infection and in controlling or treating a disease caused by a viral infection. The compounds are therefore useful in the prophylaxis of diseases such as cold sores (caused by herpes simplex 1) and genital herpes, and also in treating and alleviating the symptoms that accompany diseases caused by viruses during their active stage of infection. Typical viral infections to be prevented and treated according to this invention include HIV, Hepatitis B, papalomavirus, and reovirus. The compounds have little or no toxic effects, and accordingly are particularly well-suited for treating and controlling viral infections in children, including AIDS, as well as adults. The compounds will be formulated for convenient oral or parenteral administration, including by aerosol delivery, transdermal delivery, or even suppositories, and will be administered in an antivirally effective dose, which is that amount that is effective to prevent and/or treat the particular virus and its severity for which treatment is needed or otherwise desired. For example, the compounds will be formulated as a topical cream, or as oral capsules and administered form one to three times a day to an individual who is engaging in activities which may lead to a viral infection. Such activities include being exposed to large amounts of ultraviolet sun radiation, which often precipitates activation of herpes simplex 1, resulting in cold sores, particularly in and around the mouth.
The disclosed MEK inhibitors can also be used in combination with other clinically effective antiviral agents. Such combination therapy has been found particularly useful for treating patients suffering from HIV infections. Agents which will be commonly used in combination with the MEK inhibitors include acyclovir, AZT (azidothymidine, zidovudine), ribavirin, vidarabine, ganciclovir, dideoxyinosine (ddl), and any of a number of protease inhibitors such as nelfinavir mesylate, and retroviral antigens such as remune (described in US 5,256,767, incorporated herein by reference).
The Bal antiviral activities shown in Table 3 establish that several of the MEK inhibitors have excellent antiviral efficacy. Particularly preferred compounds to be used to treat and prevent HIV infections are 2-(2-chloro- 4-iodophenylamino)-N-cyclobutylmethoxy-3,4-difluorobenzamide (PD 185625); 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-4-fluorobenzamide (PD 203311); 2-(2-chloro-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD 185848); and 2-(2-methyl-4-iodophenylamino)-N-cyclopropylmethoxy-3,4,5- rifluorobenzamide (PD 198306). These MEK inhibitors have excellent antiviral activity in the absence of cytotoxicity.
One aspect of the invention features a method for treating or preventing a viral infection, wherein said method includes administering a MEK inhibitor before a viral infection in the patient has been confirmed. The HIV BaL/Macro data in Table 3 was obtained by adding the MEK inhibitor following activation but before HIV infection.
D. Other Embodiments
From the above disclosure and examples, and from the claims below, the essential features of the invention are readily apparent. The scope of the invention also encompasses various modifications and adaptations within the knowledge of a person of ordinary skill. Examples include a disclosed compound modified by addition or removal of a protecting group, or an ester, pharmaceutical salt, hydrate, acid, or amide of a disclosed compound. Publications cited herein are hereby incorporated by reference in their entirety.

Claims

What is claimed is:
A method for preventing and treating viral infections in mammals, said method comprising 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 disease, an anti-viral effective amount of a MEK inhibitor.
A method according to Claim 1 wherein the MEK inhibitor is 2-(2-amino- 3-methoxyphenyl)-4-oxo-4H-[l]benzopyran.
A method for preventing and treating viral infections in mammals, said method comprising 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 disease, an anti-viral effective amount of a phenyl amine compound of Formula I:
wherein:
Rl is hydrogen, hydroxy, Ci-Cg alkyl, C -Cg alkoxy, halo, trifluoromethyl, or CN; R2 is hydrogen; R3, R4, and R5 independently are hydrogen, hydroxy, halo, trifluoromethyl, Ci-C alkyl, C -Cg alkoxy, nitro, CN, or
-(O or NH)m-(CH2)n-R9, where R9 is hydrogen, hydroxy, COOH, or NRioRn; n is 0-4; m is 0 or 1 ;
RlO and R\ \ independently are hydrogen or Ci-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-C -Cg alkyl; Z is COOR7, tetrazolyl, CONR6R7, CONHNRIQRI 1, or CH2OR7; R and R7 independently are hydrogen, Ci-Cg alkyl, C2-C alkenyl,
C2-Cg alkynyl, (CO)-Cι-Cg alkyl, aryl, heteroaryl, C3-C10 cycloalkyl, or C3-C10 (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, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, Cj-C6 alkoxy, amino, nitro, -C4 alkylamino, di(CrC4)alkylamino, C3-C6 cycloalkyl, phenyl, phenoxy, C3-C5 heteroaryl or heterocyclic radical, or C3-C5 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) R2 is hydrogen; (c) R3, R-j, and R5 independently are hydrogen, fluoro, chloro, bromo, iodo, methyl, methoxy, or nitro; (d) Rio and R\ j independently are hydrogen or methyl; (e) Z is COOR7, tetrazolyl, CONReR?, CONHNR10Rπ, or CH2OR7; Re and R7 independently are hydrogen, C 1-4 alkyl, heteroaryl, or C 3.5 cycloalkyl optionally containing one or two heteroatoms selected from O, S, or NH; or R^ 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 COOR7; (g) R7 is H, pentafluorophenyl, or tetrazolyl; (h) R3, R4, and R5 are independently H, fluoro, or chloro; (i) R4 is fluoro; (j) two of R3, R4, and R 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-( 1 H-tetrazol-5-yl)-phenyl(4-iodo-2-methyl-phenyl)- amine;
(4-Iodo-2-methyl-phenyl)-[2-(lH-tetrazol-5-yl)-phenyl]amine;
[4-Nitro-2-( 1 H-tetrazol-5-yl)-phenyl-(4-iodo-2-methyl-phenyl)- amine; 4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid;
3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
5 -Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
Sodium 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoate;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
2-(4-Iodo-2-methyl-phenylamino)-5 -nitro-benzoic acid;
4-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2-(4-Iodo-2-methyl-phenylamino)-benzoic acid;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
2,3 ,5-Trifluoro-4-(4-iodo-2-methyl-phenylamino)-benzoic acid;
2-(4-Iodo-phenylamino)-5-methoxy-benzoic acid; 5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
2-(4-Iodo-2-methyl-phenylamino)-4-nitro-benzoic acid;
2-(4-Bromo-2-methyl-phenylamino)-4-fluoro-benzoic acid; 2-(2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic acid;
2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-benzoic acid;
5-Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-benzamide;
N-Ethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-( 1 H-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-pynolidin- 1 -yl-ethyl)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-pyridin-4-yl-ethyl)-benzamide;
4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-N-(3-dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-
2-methyl-phenylamino)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-morpholin-4-yl-ethyl)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin- 4-yl-ethyl)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 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-pynolidin- 1 -yl- ethyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-morpholin- 4-yl-ethyl)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- pyridin-4-ylmethyl-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin- 4-ylmethyl-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-N-(3-dimethylamino- propyl)-3 ,4-difluoro-benzamide; 4-Fluoro-2-(4-iodo-2 -methyl -phenylamino)-N-pyridin-4-ylmethyl- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- ethyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyridin- 4-yl-ethyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(3-hydroxy- propyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyrrolidin- 1 -yl-ethyl)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyl- benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-thiophen- 2-yl-ethyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-pyridin- 4-ylmethyl-benzamide;
2-(4-Bromo-2-methyl-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-Iodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl methyl- benzamide;
5 -Bromo-N- { 3 - [4-(2-hydroxy-ethyl)-piperazin- 1 -yl] -propyl } - 2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- 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 -yl- ethyl)-benzamide;
5 -Chloro-N-(3 -dimethylamino-proρyl)-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-l-yl- propyl)-benzamide;
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-2-(4-iodo-2-methyl- phenylamino)-5-nitro-benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-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-l-yl- propyl)-benzamide;
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin- 1 -yl- ethyl)-benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin- 1 -yl- ethyl)-benzamide;
N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide ; 5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; 5-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-(3-Diethylamino-propyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
N-(3-Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- 5-nitro-benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- ethyl)-benzamide;
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin- 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- ethyl)-benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl- propyl)-benzamide;
[5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- [4-(2-hydroxy-ethyl)-piperazin- 1 -yl]-methanone; N-(3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo-
2-methyl-phenylamino)-benzamide;
N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- benzamide; 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide;
5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-(2-Hydroxy-ethyl)-2-(4-iodo-2-ethyl-phenylamino)-5-nitro- benzamide;
2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- benzamide; 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide;
N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide;
N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide;
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide;
N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide;
N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Allyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide; 2-(4-Iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-5-nitro- benzamide;
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide; 5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide; N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-mtro- benzamide;
N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide;
N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-mtro- benzamide; N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohol;
[5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol;
[2-(4-Iodo-2-methyl-phenylamino)-5-nitro-phenyl]-methanol;
[5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol; and
N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide.
A method for preventing and treating viral infections in mammals, said method comprising 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 disease, an anti- viral effective amount of a phenyl amine of Formula II:
wherein:
R a is hydrogen, hydroxy, C -Cg alkyl, Cι~Cg alkoxy, halo, trifluoromethyl, or CN; R2a is hydrogen; R3a, R4a, and R5a independently are hydrogen, hydroxy, halo, trifluoromethyl, -C alkyl, Ci-C alkoxy, nitro, CN, or
(O or NH)m-(CH2)n-R9a> where Rga is hydrogen, hydroxy, CO2H or NRiOaRl la- n is 0-4; m is 0 or 1 ;
RjOa and Rl la independently are hydrogen or C -C alkyl, or taken together with the nitrogen to which they are attached can complete a 3- to 10-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S, NH, or
N-Ci-Cg alkyl;
R a is hydrogen, Ci-C alkyl, (CO)-Cι-Cg alkyl, aryl, aralkyl, or
C3-C10 cycloalkyl; R7a is hydrogen, Ci-C alkyl, C2-C alkenyl, C2-C alkynyl, C3-C10 (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NRc^; and wherein any of the foregoing alkyl, alkenyl, aryl, heteroaryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, Cj- alkoxy, amino, nitro, Cι-C4 alkylamino, di(d- C4)alkylamino, C3-C6 cycloalkyl, phenyl, phenoxy, C3-C5 heteroaryl or heterocyclic radical, or C3-C5 heteroaryloxy or heterocyclic radical-oxy; or R a and R7a taken together with the N to which they are attached can complete a 5- to 10-membered cyclic ring, optionally containing one, two, or three additional heteroatoms selected from O, S, or NRiOa^l la» 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) Rla is H, methyl, fluoro, or chloro; (b) R2a is H; R3a, R4a, and R5aare each H, Cl, nitro, or F; (c) R^ is H; (d) R a 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: R4a is F at the 4 position, para to the CO-N-R6a-OR a group and meta to the bridging nitrogen; at least one of R3a and R5a is F or Cl; and Rla is methyl or chloro.
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; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-( 1 -methylprop- 2-ynyloxy)-benzamide;
3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -phenylprop- 2-ynyloxy)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-
5-phenylpent-2-en-4-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop- 2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(propoxy)- benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclobutyloxy)- benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-thienylmethoxy)-benzamide; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-methyl-prop-
2-enyloxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-phenoxyethoxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)- benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-3-ynyloxy)- benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopentyloxy)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(3-(2-fluorophenyl)-prop-2-ynyloxy)-benzamide;
5-Bromo-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (n-propoxy)-benzamide;
5-Bromo-3,4-difluoro-N-(furan-3-ylmethoxy)-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-N-(but-2-enyloxy)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide
5-Bromo-N-butoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(3-methyl-but-2-enyloxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-methyl-pent-2-en-4-ynyloxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-benzyl)-N- [5-(3-methoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop- 2-ynyloxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- [3-(3-methoxy-phenyl)-prop-2-ynyloxy]-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(thiopen-2-ylmethoxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (pyridin-3-ylmethoxy)-benzamide;
5-Bromo-3-4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3 -(2-fluorophenyl)-prop-2-ynyloxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (ethoxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(isopropoxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-but- 3 -ynyloxy)-benzamide;
5-Chloro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydro-pyran- 2-yloxy)-benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy- benzamide;
4-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide;
5-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide; 5 -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tefr ahydropyran-
2-yloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (3-phenylprop-2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (3 -furylmethoxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (2-thienylmethoxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but- 3-ynyloxy)-benzamide; 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-methyl- prop-2-enyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but- 2-enyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(methoxy)- benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(ethoxy)- benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (cyclobutoxy)-benzamide; 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(isopropoxy)- benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (2-phenoxyethoxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclopropyl- methoxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(n-propoxy)- benzamide; 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-( 1 -methyl - prop-2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (3 -(3 -fluorophenyl)-prop-2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (4,4-dimethylpent-2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (cyclopentoxy)-benzamide;
3,4,5-Trifluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5 -Bromo-3 ,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N- hydroxy-benzamide;
N-Hydroxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzamide; 3,4,5-Trifluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy- benzamide;
5-Chloro-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N- hydroxy-benzamide;
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide;
2-(2-Fluoro-4-iodo-phenylamino)-N-hychOxy-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; 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 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 and treating viral infections in mammals, said method comprising 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 disease, an anti-viral effective amount of a compound selected from:
2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy- 3,4-difluorobenzamide (PD184352); 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide
(PD170611);
2-(2-Methyl-4-iodophenylamino)-N-hydroxy-3,4-difluoro- 5-bromobenzamide (PD171984);
2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy- 3,4-difluoro-5-bromobenzamide (PD177168);
2-(2-Methyl-4-iodophenylamino)-N-cyclobutylmethoxy- 3,4-difluoro-5-bromobenzamide (PD 180841);
2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy- 3,4-difluoro-5-bromobenzamide (PD 184161); 2-(2-Chloro-4-iodophenylamino)-N-hydroxy-3 ,4-difluoro-
5-bromobenzamide (PD184386);
2-(2-Chloro-4-iodophenylamino)-N-cyclobutylmethoxy- 3,4-difluorobenzamide (PD 185625);
2-(2-Chloro-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD 185848);
2-(2-Methyl-4-iodophenylamino)-N-hydroxy- 3,4-difluorobenzamide(PD 188563);
2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy- 3,4,5-trifluorobenzamide (PD 198306); and 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-
4-fluorobenzamide (PD 203311).
12. A method according to Claim 1, 3, or 6 wherein the viral infection to be prevented or treated is HIV.
13. A method according to Claim 1 , 3, or 6 wherein the viral infection to be prevented or treated 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 (PD170611);
2-(2-Methyl-4-iodophenylamino)-N-hydroxy-3,4-difluoro- 5-bromobenzamide (PD171984);
2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy- 3 ,4-difluoro-5-bromobenzamide (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-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 a viral infection.
EP99966522A 1999-01-07 1999-12-21 Antiviral method using mek inhibitors Withdrawn EP1140067A1 (en)

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