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EP1140067A1 - Methode antivirale utilisant des inhibiteurs de mek - Google Patents

Methode antivirale utilisant des inhibiteurs de mek

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Withdrawn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)
English (en)
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/fr
Withdrawn legal-status Critical Current

Links

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.

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Abstract

Cette invention se rapporte à une méthode de prévention ou de traitement d'infections virales consistant à administrer à un patient nécessitant un tel traitement une quantité efficace d'un inhibiteur des kinases MEK, et notamment une phénylamine représentée par les formules (I) et (II).
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ZA200104000B (en) 2002-08-16
WO2000040237A1 (fr) 2000-07-13
HUP0104933A2 (hu) 2002-04-29
CA2358438A1 (fr) 2000-07-13
AU2203800A (en) 2000-07-24
HUP0104933A3 (en) 2003-12-29
IL144103A0 (en) 2002-05-23
JP2002534381A (ja) 2002-10-15

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