WO2000040235A2 - Treatment of asthma with mek inhibitors - Google Patents

Treatment of asthma with mek inhibitors Download PDF

Info

Publication number
WO2000040235A2
WO2000040235A2 PCT/US1999/030419 US9930419W WO0040235A2 WO 2000040235 A2 WO2000040235 A2 WO 2000040235A2 US 9930419 W US9930419 W US 9930419W WO 0040235 A2 WO0040235 A2 WO 0040235A2
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
phenylamino
iodo
benzamide
difluoro
Prior art date
Application number
PCT/US1999/030419
Other languages
French (fr)
Other versions
WO2000040235A3 (en
Inventor
Alexander James Bridges
David Thomas Dudley
James Leslie Mobley
Alan Robert Saltiel
Original Assignee
Warner-Lambert Company
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 Company filed Critical Warner-Lambert Company
Priority to US09/889,091 priority Critical patent/US6696440B1/en
Priority to JP2000591992A priority patent/JP2002534380A/en
Priority to AT99968153T priority patent/ATE292462T1/en
Priority to EP99968153A priority patent/EP1140062B1/en
Priority to CA002350234A priority patent/CA2350234A1/en
Priority to BR9916785-9A priority patent/BR9916785A/en
Priority to AU24830/00A priority patent/AU2483000A/en
Priority to DE69924641T priority patent/DE69924641D1/en
Publication of WO2000040235A2 publication Critical patent/WO2000040235A2/en
Publication of WO2000040235A3 publication Critical patent/WO2000040235A3/en

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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • This invention relates to a method for preventing and treating asthma 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) Kinases. These are enzymes that regulate phosphorylation of substrates in mammals.
  • MEK kinases which are groups of MAP (mitogen- associated protein kinase) and Erk (extracellular signal-regulated) Kinases.
  • Asthma is a heterogeneous disorder of the airways that afflicts millions of people. Airway inflammation, hyperresponsiveness, and obstruction characterize the condition. The disease often causes spasms of the bronchial smooth muscle system, and affects both the upper and lower respiratory tracts. There are several forms of asthma, characterized by varying degrees of severity. Mild asthma, for example, is defined as brief episodes of wheezing, with or without dyspnea or cough. Moderately severe asthma is defined as wheezing and dyspnea, and can be with or without cough and expectoration, but generally interferes with daily activities and/or sleeping.
  • Severe asthma is characterized by incapacitation due to dyspnea, and the afflicted patient typically is unable to eat or sleep normally, is very anxious, and is often exhausted.
  • a condition known as status asthmaticus is the most severe form of asthma, and generally requires intensive hospital care, and may even prove fatal. The disease may occur as a result of both allergic and nonallergic mechanisms.
  • An object of this invention is therefore to provide a new method for preventing and treating asthmatic conditions.
  • This invention provides a method of preventing and treating asthma, said method comprising the step of administering to a patient an antiasthmatic- effective amount of a MEK inhibitor.
  • Selective MEK inhibitors are 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 or treating asthma by administering a MEK inhibitor.
  • the invention provides a method for preventing and/or treating asthma 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:
  • Rj is hydrogen, hydroxy, Cj-Cg alkyl, Cj-Cg alkoxy, halo, trifluoromethyl, or CN.
  • R2 is hydrogen.
  • R3, R4, and R5 are independently selected from hydrogen, hydroxy, halo, trifluoromethyl, Cj-Cg alkyl, Cj-Cg alkoxy, nitro, CN, and -(O or NH) m -(CH2)
  • n -R9- R9 is hydrogen, hydroxy,
  • R ⁇ 0 and R ⁇ ⁇ are independently selected from hydrogen and Cj-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N-(C ⁇ -Cg alkyl).
  • Z is COORy, tetrazolyl, CONR 6 R 7 , CONHNR 10 R l l 5 or CH 2 OR 7 .
  • R6 and R7 independently are hydrogen, C ⁇ -Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl,
  • any of the foregoing alkyl, alkenyl, aryl, heteroaryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, -C ⁇ alkoxy, amino, nitro, C C 4 alkylamino, di(C ⁇ -C 4 )alkylamino, C 3 -C 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) Ri 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) Rio and Rn independently are hydrogen or methyl; (e) Z is COOR 7 , tetrazolyl, CONR o R 7 , CONHNRioR ⁇ , or CH 2 OR 7 ; Re and R 7 independently are hydrogen, C ⁇ alkyl, heteroaryl, or C 3- 5 cycloalkyl optionally containing one or two heteroatoms selected from O, S, or NH; or R and R 7 together with the nitrogen to which they are attached complete a 5-6 member cyclic ring optionally containing 1 or 2 additional heteroatoms selected from O, NH or N-alkyl; and wherein any of
  • the 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, Cj-Cg alkoxy, halo, trifluoromethyl, or CN.
  • R2 a is hydrogen.
  • Each of R10a and R1 ⁇ a is independently hydrogen or Cj-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3- to 10-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S, NH, or N-(C ⁇ -Cg alkyl).
  • Rf ⁇ is hydrogen, C1 -Cg alkyl, (CO)-(C ⁇ -Cg alkyl), aryl, aralkyl, or C3-C10 cycloalkyl.
  • Rj a is hydrogen, Cj-Cg alkyl, C2"Cg alkenyl, C2-C alkynyl, C3-C 10 (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NRc ⁇ ).
  • any of the foregoingany 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, Cj-C 4 alkylamino, di(C ⁇ -C 4 )alkylamino, C 3 -C 6 cycloalkyl, phenyl, phenoxy, C 3 - heteroaryl or heterocyclic radical, or C 3 -C 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 three additional heteroatoms selected from O, S, or NRj ⁇ aRl la-
  • the invention also encompasses pharmaceutically acceptable salts, esters, amides or prodrugs of each of the disclosed compounds.
  • R la is H, methyl, fluoro, or chloro
  • R 2a is H
  • R 3a , R ⁇ , and R 5a are each H, Cl, nitro, or F
  • R ⁇ is H
  • R a is methyl, ethyl, 2-propenyl, propyl, butyl, pentyl, hexyl, cyclopropylmethyl, cyclobutyl methyl, cyclopropylmethyl, or cyclopropylethyl
  • the 4' position is I, rather than Br
  • R 4a is F at the 4 position, para to the CO-N-R 6a -OR a group and meta to the bridging nitrogen;
  • R 3a or R 5a is F;
  • at least one of R 3a , i a , 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:
  • 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-
  • 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-
  • the invention further provides methods of synthesis and synthetic intermediates.
  • a mitotic inhibitor is administered to a patient suffering from cancer and in need of treatment in combination with a selective MEK inhibitor selected from: 2-(2-Chloro- 4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide (PD 184352); 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD 170611);
  • 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-3,4-difluoro-5-bromobenzamide (PD171984), a more preferred compound; 2-(2-Methyl-4-iodophenylamino)-N- cyclopropylmethoxy-3,4-difluoro-5-bromobenzamide (PDl 77168); 2-(2-Methyl- 4-iodophenylamino)-N-cyclobutylmethoxy-3,4-difluoro-5-bromobenzamide (PD 180841 ); 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-
  • 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.
  • the benzoic acid derivative of PD 198306 is 2-(2-Methyl-4-iodophenylamino)-3,4,5-trifluorobenzoic acid.
  • This invention provides a method of preventing or treating asthma in a patient which comprises administering to a patient suffering from asthma and in need of treatment, or to a patient at risk for developing an asthmatic attack, an anti-asthmatic effective amount of a MEK inhibitor.
  • the invention provides a method of preventing and treating all forms of asthma and relieving the symptoms that accompany the disease.
  • the invention is preferably practiced by administering a phenyl amine MEK inhibitor of Formula I or Formula II.
  • Such MEK phenyl amine compounds are specific MEK 1 and MEK 2 inhibitors, meaning that they inhibit these enzymes without inhibiting other enzymes to a great extent.
  • 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.
  • the mammals to be treated according to this invention are patients who have developed asthma and are suffering from the symptoms associated with disease, or who are at risk for developing the disease, for example having a family history of asthma. Those skilled in the medical art are readily able to identify individual patients, particularly children, who are afflicted with asthma, as well as those who are susceptible to developing the disease.
  • 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-
  • 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.
  • 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, 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,
  • 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-(mo ⁇ holin-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
  • Alkynyl means a straight or branched carbon chain having at least one triple bond. Typical alkynyl groups include prop-2-ynyl, 2-methyl-hex-5-ynyl, 3,4-dimethyl-hex-5-ynyl, and 2-ethyl-but-3-ynyl.
  • the alkynyl groups can be substituted as the alkyl and alkenyl groups, for example, by aryl, aryloxy, heteroaryl, or heteroaryloxy, for example 4-(2-fluorophenyl)-but-3-ynyl, 3-methyl-5-thienylpent-4-ynyl, 3-phenoxy-hex-4-ynyl, and 2-furyloxy-3-methyl- hex-4-ynyl.
  • the alkenyl and alkynyl groups can have one or more double bonds or triple bonds, respectively, or a combination of double and triple bonds.
  • 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, mo ⁇ holinyl, 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-thienylmo ⁇ holine-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.
  • a selective MEK 1 or MEK 2 inhibitor has an IC 50 for MEK 1 or MEK 2 that is at least one-fiftieth (1/50) that of its IC 0 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- named enzymes.
  • the MEK inhibitors of the present method can be administered to a patient as part of a pharmaceutically acceptable composition.
  • the compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly,or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • 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 abso ⁇ tion of the injectable pharmaceutical form can be brought about by the use of agents delaying abso ⁇ tion, 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
  • abso ⁇ tion accelerators as for example, quaternary ammonium compounds
  • lubricants as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof.
  • 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, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate,
  • 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, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
  • 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
  • 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 inco ⁇ orated herein by reference.)
  • Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include C ⁇ -Cg alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods. Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary Ci-Cg alkyl amines and secondary Cj-C6 dialkyl amines wherein the alkyl groups are straight or branched chain.
  • 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 Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are inco ⁇ orated 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 pu ⁇ oses 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 HNR6R7.
  • the reaction is carried out by reacting approximately equimolar quantities of the benzoic acid and amine in an unreactive organic solvent in the presence of a coupling reagent.
  • Typical solvents are chloroform, dichloromethane, tetrahydrofuran, benzene, toluene, and xylene.
  • Typical coupling reagents include DCC, EEDQ, PyBrOP, and PyBOP. The reaction is generally complete after about 10 minutes to about 2 hours when carried out at a temperature of about 0°C to about 60°C.
  • the product amide is readily isolated by removing the reaction solvent, for instance by evaporation, and further purification can be accomplished by normal methods such as chromatography, crystallization, or distillation.
  • the benzyl alcohols of the invention, compounds of Formula I where Z is CH2OR6 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-(4-iodo-2-methylphenylamino benzoic acid To a stirring solution comprised of 3.16 g (0.0133 mol) of 2-amino-5- iodotoluene in 5 mL of tetrahydrofuran at -78°C was added 10 mL (0.020 mol) of a 2.0 M lithium diisopropylamide in tetrahydrofuran heptane/ethenylbenzene (Aldrich) solution.
  • the 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
  • Step b Preparation of 5-chloro-2-fluoro-benzaldehyde 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 HNR6 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.
  • the first set of experiments was designed to determine whether the MEK inhibitors could prevent antigen-induced production of IL-5 by the ONA-primed splenocytes in vitro.
  • IL-5 is required for the differentiation, migration, and survival of pulmonary eosinophils, which are thought to be responsible for much of the pathology associated with human asthma.
  • ONA-sensitized mice were sacrificed by cervical dislocation 14 days after sensitization (Day 14), the spleens were excised and disaggregated, and the erythrocytes were lysed. The splenocytes were washed and resuspended at 5 x 10 > cells/mL in complete medium consisting of
  • RPMI 1640 Gibco BRL, Gaithersburg, MD
  • 10% heat-inactivated fetal calf serum Hyclone, Logan, UT
  • 55 ⁇ M 2-mercaptoethanol 50 U/mL penicillin G
  • 50 ⁇ g/mL streptomycin sulfate 50 ⁇ g/mL streptomycin sulfate
  • 2 mM L-glutamine Gibco BRL
  • the splenocytes were then cultured at 37°C in the presence of 200 ⁇ g/mL ON A.
  • MEK inhibitors were also added to the cultures from sterile 10 mM stock solutions (in
  • mice 1 x 10 > cells/mL in sterile saline.
  • Groups of five na ⁇ ve (unsensitized) C57BL/c mice were injected i.p. with 200 ⁇ L of the cell suspension (2 x 10 ⁇ cells).
  • the recipient mice were challenged with a 12-minute inhalation of an aerosol formulation of 1.5% OVA in saline (weight/volume), the mist being produced by a nebulizer (small particle generator model SPAG-2, ICN Pharmaceuticals, Costa Mesa, CA).
  • the mice were anesthetized with an i.p. injection of an anesthetic mixture comprising Ketamine, acepromazine, and xylazine.
  • the trachea of each mouse was exposed and cannulated.
  • the lungs and upper airways were lavaged with 0.5 mL of cold
  • BAL bronchoalveolar lavage
  • the cell suspension (100 ⁇ L) was centrifuged in a cytospin (Shandon Southern Instruments, Sewickley, PA) and stained with Diff Quick to distinguish neutrophil, eosinophil, monocyte, and lymphocyte subsets.
  • the number of eosinophils in the BAL fluid was determined by multiplying the percentage of eosinophils by the total cell count.
  • mice were sensitized with OV A/aluminum hydroxide on Day 0 as described above. On Day 14, the mice were challenged by aerosol with 1.5% OVA, as described above for the adoptive-transfer recipients.
  • One group of eight sensitized mice was dosed orally with vehicle (0.5% hydroxypropylmethylcellulose/0.25% TWEEN-80).
  • Other groups of sensitized mice (8 mice per group) were given oral doses of a
  • MEK inhibitor The test compound was dissolved in the vehicle, and the volume for each dosage was adjusted to 200 ⁇ L, so that each test animal received the same oral volume.
  • the MEK inhibitor was administered starting on Day 13 (ie, 13 days after initial sensitization and 1 day prior to aerosol challenge), and continued daily through Day 16 (4 days total).
  • the MEK inhibitor was administered starting on Day 7 (ie, 7 days after initial sensitization and 7 days prior to aerosol challenge), and continued daily through Day 16 (9 days total).
  • Day 17 of each experiment 17 days following the initial OVA challenge, and 3 days after the OVA aerosol challenge
  • all animals including controls were anesthetized, cannulated, and lavaged as previously described.
  • the number of BAL eosinophils was determined as described above.
  • the selective MEK inhibitors are active in inhibiting a model of asthma in mice.
  • the compounds have little or no toxic effects, and accordingly are particularly well-suited for treating and controlling asthma in children, 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 antiasthmatic effective dose, which is that amount that is effective to treat the particular asthma severity for which treatment is needed or otherwise desired.
  • the selective MEK inhibitors are active in both inhibiting and controlling the asthmatic disease, for example, prior to actual challenge and following challenge.
  • the compounds are therefore useful in the prophylaxis of asthma, and also in treating and alleviating the symptoms that accompany the disease during its active stage.
  • the compounds have little or no toxic effects, and accordingly are particularly well-suited for treating and controlling asthma in children, 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 antiasthmatic effective dose, which is that amount that is effective to treat the particular asthma severity for which treatment is needed or otherwise desired.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

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

Description

TREATMENT OF ASTHMA WITH MEK INHIBITORS
FIELD OF THE INVENTION
This invention relates to a method for preventing and treating asthma 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) Kinases. These are enzymes that regulate phosphorylation of substrates in mammals.
BACKGROUND OF THE INVENTION
Asthma is a heterogeneous disorder of the airways that afflicts millions of people. Airway inflammation, hyperresponsiveness, and obstruction characterize the condition. The disease often causes spasms of the bronchial smooth muscle system, and affects both the upper and lower respiratory tracts. There are several forms of asthma, characterized by varying degrees of severity. Mild asthma, for example, is defined as brief episodes of wheezing, with or without dyspnea or cough. Moderately severe asthma is defined as wheezing and dyspnea, and can be with or without cough and expectoration, but generally interferes with daily activities and/or sleeping. Severe asthma is characterized by incapacitation due to dyspnea, and the afflicted patient typically is unable to eat or sleep normally, is very anxious, and is often exhausted. A condition known as status asthmaticus is the most severe form of asthma, and generally requires intensive hospital care, and may even prove fatal. The disease may occur as a result of both allergic and nonallergic mechanisms.
While there are several treatments available for relieving the symptoms and discomfort associated with asthma, there are no cures. Moreover, the current treatments often cause side effects that exacerbate the discomfort and precipitate other debilitating conditions. Mild asthma generally is treated with beta- adrenergic drugs, as well as antihistamines, especially in the case of children, to prevent or abort sporadic episodes. Moderately severe and severe asthma are generally treated with adrenergic agents and bronchodilators, as well as corticosteroids. Other actions caused by antiasthmatic agents which limit their widespread use include headache, fatigue, dry mouth, nervousness, and in some cases addiction and substance abuse. Recent advances in the understanding of the pathogenesis and treatment of asthma is discussed more fully by Grayson et al.,
The Mount Sinai Journal of Medicine, Sept. 1998;65(4):246-256.
Because asthma is so prevalent in both children and adults, there is an ongoing need for agents that can treat the disease, or at least relieve the symptoms that accompany the disease, without causing undesirable side effects. We have now discovered that MEK inhibitors are particularly useful for treating asthma and relieving the symptoms that accompany the disease. An object of this invention is therefore to provide a new method for preventing and treating asthmatic conditions.
SUMMARY OF THE INVENTION
This invention provides a method of preventing and treating asthma, said method comprising the step of administering to a patient an antiasthmatic- effective amount of a 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 preferred embodiment, the invention provides a method for preventing or treating asthma by administering a MEK inhibitor. In a further embodiment, the invention provides a method for preventing and/or treating asthma 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:
Figure imgf000005_0001
In Formula (I), Rj is hydrogen, hydroxy, Cj-Cg alkyl, Cj-Cg alkoxy, halo, trifluoromethyl, or CN. R2 is hydrogen. R3, R4, and R5 are independently selected from hydrogen, hydroxy, halo, trifluoromethyl, Cj-Cg alkyl, Cj-Cg alkoxy, nitro, CN, and -(O or NH)m-(CH2)n-R9- R9 is hydrogen, hydroxy,
COOH, or NRj QRI 1 ; n is 0-4; m is 0 or 1. Each of R\ 0 and R\ \ is independently selected from hydrogen and Cj-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N-(Cι -Cg alkyl). Z is COORy, tetrazolyl, CONR6R7, CONHNR10Rl l 5 or CH2OR7. R6 and R7 independently are hydrogen, C^-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl,
(CO)-Cj-Cg alkyl, aryl, heteroaryl, C3-C10 cycloalkyl, or C3-C10 (cycloalkyl optionally containing one, two, or three heteroatoms selected from O, S, NH, or N alkyl); or R5 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, -Cβ alkoxy, amino, nitro, C C4 alkylamino, di(Cι-C4)alkylamino, C3-C 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) Ri is hydrogen, methyl, methoxy, fluoro, chloro, or bromo; (b) R2 is hydrogen; (c) R3, R4, and R5 independently are hydrogen, fluoro, chloro, bromo, iodo, methyl, methoxy, or nitro; (d) Rio and Rn independently are hydrogen or methyl; (e) Z is COOR7, tetrazolyl, CONRoR7, CONHNRioRπ, or CH2OR7; Re and R7 independently are hydrogen, C \→\ alkyl, heteroaryl, or C 3-5 cycloalkyl optionally containing one or two heteroatoms selected from O, S, or NH; or R and R7 together with the nitrogen to which they are attached complete a 5-6 member cyclic ring optionally containing 1 or 2 additional heteroatoms selected from O, NH or N-alkyl; and wherein any of the foregoing alkyl or aryl groups can be unsubstituted or substituted by halo, hydroxy, methoxy, ethoxy, or heteroaryloxy (such as 2,3,4,5,6-pentafluorophenyl); (f) Z is COOR ; (g) R is H, pentafluorophenyl, or tetrazolyl; (h) R3, R4, and R5 are independently H, fluoro, or chloro; (i) R4 is fluoro; (j) two of R3, R4, and R5 are fluoro; or (k) or combinations of the above. 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-(lH-tetrazol-5-yl)-phenyl-(4-iodo-2-methyl-phenyl)-amine (4-iodo-2-methyl-phenyl)-[2-( 1 H-tetrazol-5-yl)-phenyl]amine
[4-nitro-2-(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-benzoic acid
5-Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-benzamide
N-Ethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(lH-tetrazol-5-yl)-benzamide 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-phenyl£imino)-N-(2-pyrrolidin-l- 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-mo holin-4-yl-ethyl)- benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -piperidin- 1 -yl-propyl)- benzamide 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -piperidin- 1 -yl-propyl)- benzamide
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thiophen-2-yl-ethyl)- benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-l-yl-ethyl)- benzamide 2-(4-Bromo-2-methyl-phenylarnino)-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- 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-l-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- 1 -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-l-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-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 FORMULA (I) COMPOUND TABLE (continued, page 7 of 10)
5-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylarnino)- 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-moφholin-4-yl-ethyl)- benzamide 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(3 -piperidin- 1-yl-propyl)- benzamide [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(2 or 3-hydroxy- pyrrolidin-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- 1 -yl-propyl)- benzamide [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4-(2-hydroxy-ethyl)- piperazin- 1 -yl)-methanone N-(3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo-2-methyl- phenyl,amino)- benzamide
N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide FORMULA (I) COMPOUND TABLE (continued, page 8 of 10)
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide
5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide N-(2-Hydroxy-ethyl)-2-(4-iodo-2-ethyl-phenylamino)-5-nitro-benzamide 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl-benzamide
5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide
N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide FORMULA (I) COMPOUND TABLE (continued, page 9 of 10)
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Allyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-benzamide 2-(4-Iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-5-nitro-benzamide 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide
N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide 5 -Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-benzamide
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl-benzamide
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide FORMULA (I) COMPOUND TABLE (continued, page 10 of 10)
N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide
5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfarnoyl-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)-phenyl]-methanol [2-(4-Iodo-2-methyl-phenylamino)-5-nitro-phenyl]-methanol [5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide.
In another preferred embodiment, the MEK inhibitor is a compound of Formula II
Figure imgf000016_0001
In Formula (II), R\a is hydrogen, hydroxy, Cj-Cg alkyl, Cj-Cg 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-Cg alkoxy, nitro, CN, and (O or NH)m-(CH2)n-R9a- R9a is hydrogen, hydroxy, CO2H or NRjOaRl la» n is 0~4; and m is 0 or 1. Each of R10a and R1 ιa is independently hydrogen or Cj-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3- to 10-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S, NH, or N-(Cι-Cg alkyl). Rfø is hydrogen, C1 -Cg alkyl, (CO)-(Cι-Cg alkyl), aryl, aralkyl, or C3-C10 cycloalkyl. Rja is hydrogen, Cj-Cg alkyl, C2"Cg alkenyl, C2-C alkynyl, C3-C 10 (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NRc^). In Formula (II), any of the foregoingany of the foregoing alkyl, alkenyl, aryl, heteroaryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, Cι-C6 alkoxy, amino, nitro, Cj-C4 alkylamino, di(Cι-C4)alkylamino, C3-C6 cycloalkyl, phenyl, phenoxy, C3- heteroaryl or heterocyclic radical, or C3-C heteroaryloxy or heterocyclic radical-oxy; or Rga 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 three additional heteroatoms selected from O, S, or NRjøaRl la- The invention also encompasses pharmaceutically acceptable salts, esters, amides or prodrugs of each of the disclosed compounds. Preferred embodiments of Formula (II) are those structures wherein:
(a) Rla is H, methyl, fluoro, or chloro; (b) R2a is H; R3a, R^, 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; (e) the 4' position is I, rather than Br; (f) R4a is F at the 4 position, para to the CO-N-R6a-OR a group and meta to the bridging nitrogen;
(f) R3a or R5a is F; (g) at least one of R3a, ia, 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-ynyloxy)- benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-phenylprop-2-ynyloxy)- benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-5-phenylpent-2-en-
4-ynyloxy)-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(propoxy)-benzamide
FORMULA (II) COMPOUND TABLE (continued, page 2 of 7)
,4-Difiuoro-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 -yny loxy)-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenyl.amino)-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 -methyl-pent-2-en-4-ynyloxy] -benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)- benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-[3-(3-methoxy- phenyl)-prop-2-ynyloxy] -benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(thiopen-
2-ylmethoxy)-benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(pyridin-
3 -ylmethoxy)-benzamide -Bromo-3-4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-(2-fluorophenyl)- prop-2-ynyloxy)-benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(ethoxy)-benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(cyclopropylmethoxy)-benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(isopropoxy)- benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-but-3-ynyloxy)- benzamide -Chloro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide -Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydro-pyran-2-yloxy)- benzamide -Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy-benzamide -Bromo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide -Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide -Iodo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydropyran-2-yloxy)- benzamide FORMULA (II) COMPOUND TABLE (continued, page 4 of 7) ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3-phenylprop-2-ynyloxy)- benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3-furylmethoxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-thienylmethoxy)- benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but-3-ynyloxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-methyl-prop-2-enyloxy)- benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but-2-enyloxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(methoxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(ethoxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclobutoxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(isopropoxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)- benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(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-berιzamide 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 -Fluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide ,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide -(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide -(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-benzamide -(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 (PD 184352); 2-(2-Methyl-4-iodophenylamino)-N- hydroxy-4-fluorobenzamide (PD 170611); 2-(2-Methyl-4-iodophenylamino)-N- hydroxy-3,4-difluoro-5-bromobenzamide (PD 171984); 2-(2-Methyl- 4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-bromobenzamide
(PD 177168); 2-(2-Methyl-4-iodophenylamino)-N-cyclobutylmethoxy- 3,4-difluoro-5-bromobenzamide (PD 180841); 2-(2-Chloro-4-iodophenylamino)- N-cyclopropylmethoxy-3,4-difluoro-5-bromobenzamide (PD 184161); 2-(2-Chloro-4-iodophenylamino)-N-hydroxy-3,4-difluoro-5-bromobenzamide (PD 184386); 2-(2-Chloro-4-iodophenylamino)-N-cyclobutylmethoxy-
3,4-difluorobenzamide (PD 185625); 2-(2-Chloro-4-iodophenylamino)-N- hydroxy-4-fluorobenzamide (PD 185848); 2-(2-Methyl-4-iodophenylamino)-N- hydroxy-3,4-difluorobenzamide (PD 188563); 2-(2-Methyl-4-iodophenylamino)- N-cyclopropylmethoxy-3,4,5-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.
Other features and advantages of the invention are apparent from the detailed description, examples, and claims set forth.
In a further preferred embodiment of this invention, a mitotic inhibitor is administered to a patient suffering from cancer and in need of treatment in combination with a selective MEK inhibitor selected from: 2-(2-Chloro- 4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide (PD 184352); 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD 170611);
2-(2-Methyl-4-iodophenylamino)-N-hydroxy-3,4-difluoro-5-bromobenzamide (PD171984), a more preferred compound; 2-(2-Methyl-4-iodophenylamino)-N- cyclopropylmethoxy-3,4-difluoro-5-bromobenzamide (PDl 77168); 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. DETAILED DESCRIPTION OF THE INVENTION
This invention provides a method of preventing or treating asthma in a patient which comprises administering to a patient suffering from asthma and in need of treatment, or to a patient at risk for developing an asthmatic attack, an anti-asthmatic effective amount of a MEK inhibitor. The invention provides a method of preventing and treating all forms of asthma and relieving the symptoms that accompany the disease. The invention is preferably practiced by administering a phenyl amine MEK inhibitor of Formula I or Formula II. Such MEK phenyl amine compounds are specific MEK 1 and MEK 2 inhibitors, meaning that they inhibit these enzymes without inhibiting other enzymes to a great extent.
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. The mammals to be treated according to this invention are patients who have developed asthma and are suffering from the symptoms associated with disease, or who are at risk for developing the disease, for example having a family history of asthma. Those skilled in the medical art are readily able to identify individual patients, particularly children, who are afflicted with asthma, as well as those who are susceptible to developing the disease.
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-(moφholin-4-yl)propyl.
"Alkenyl" means a straight or branched carbon chain having one or more double bonds. Examples include but-2-enyl, 2 -methyl -prop-2-enyl, 1,1-dimethyl- hex-4-enyl, 3-ethyl-4-methyl-pent-2-enyl, and 3-isopropyl-pent-4-enyl. The alkenyl groups can be substituted with halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy, heteroaryl, or heteroyloxy, for example
2-bromoethenyl, 3-hydroxy-2-butenyl, 1-aminoethenyl, 3-phenylprop-2-enyl, 6-thienyl-hex-2-enyl, 2-furyloxy-but-2-enyl, and 4-naphthyloxy-hex-2-enyl.
"Alkynyl" means a straight or branched carbon chain having at least one triple bond. Typical alkynyl groups include prop-2-ynyl, 2-methyl-hex-5-ynyl, 3,4-dimethyl-hex-5-ynyl, and 2-ethyl-but-3-ynyl. The alkynyl groups can be substituted as the alkyl and alkenyl groups, for example, by aryl, aryloxy, heteroaryl, or heteroaryloxy, for example 4-(2-fluorophenyl)-but-3-ynyl, 3-methyl-5-thienylpent-4-ynyl, 3-phenoxy-hex-4-ynyl, and 2-furyloxy-3-methyl- hex-4-ynyl. The alkenyl and alkynyl groups can have one or more double bonds or triple bonds, respectively, or a combination of double and triple bonds. For example, typical groups having both double and triple bonds include hex-2-en- 4-ynyl, 3-methyl-5-phenylpent-2-en-4-ynyl, and 3-thienyloxy-hex-3-en-5-ynyl. The term "cycloalkyl" means a nonaromatic ring or fused rings. Examples include cyclopropyl, cyclobutyl, cyclopenyl, cyclooctyl, bicycloheptyl, adamantyl, and cyclohexyl. The ring can optionally contain one, two, or three heteroatoms selected from O, S, or N. Such groups include tetrahydrofuryl, tetrahydropyrrolyl, octahydrobenzofuranyl, moφholinyl, piperazinyl, pyrrolidinyl, piperidinyl, octahydroindolyl, and octahydrobenzothiofuranyl. The cycloalkyl groups can be substituted with the same substituents as an alkyl and alkenyl groups, for example, halo, hydroxy, aryl, and heteroaryloxy. Examples include 3-hydroxycyclohexyl, 2-aminocyclopropyl, 2-phenylpyrrolidinyl, and 3-thienylmoφholine-l-yl. 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 IC50 for MEK 1 or MEK 2 that is at least one-fiftieth (1/50) that of its IC 0 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 IC50or one or more of the above- named enzymes.
B. Administration and Formulation
The MEK inhibitors of the present method can be administered to a patient as part of a pharmaceutically acceptable composition. The compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly,or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absoφtion of the injectable pharmaceutical form can be brought about by the use of agents delaying absoφtion, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absoφtion accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and
(i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well- known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like. Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component. Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalamic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
The compounds of the present method can be administered to a patient at dosage levels in the range of about 0.1 to about 1000 mg per day. For a normal human adult having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kg of body weight per day is preferable. The specific dosage used, however, can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well- known to those skilled in the art.
The compounds of the present method can be administered as pharmaceutically acceptable salts, esters, amides, or prodrugs. The term "pharmaceutically acceptable salts, esters, amides, and prodrugs" as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
The term "salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, S.M. Berge, et al., "Pharmaceutical Salts," J Pharm. Sci.. 1977;66:1-19 which is incoφorated herein by reference.)
Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include C^-Cg alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods. Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary Ci-Cg alkyl amines and secondary Cj-C6 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5 or 6 membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1 -C3 alkyl primary amines and C1 -C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incoφorated herein by reference.
In addition, the compounds of the present method can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the puφoses of the present invention. Some of the compounds of the present method can exist in different stereoisometric forms by virtue of the presence of chiral centers. It is contemplated that all stereoisometric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of this invention.
C. Synthesis
The examples presented below are intended to illustrate particular embodiments of the invention and are not intended to limit the scope of the specification, including the claims, in any way. After the priority date of the present disclosure, related syntheses and MEK inhibition data were also published in WO 99/01421 and WO 99/01426, hereby incoφorated by reference.
The 2-(4-bromo and 4-iodo phenylamino)-benzoic acid derivatives of Formula I can be prepared from commercially available starting materials utilizing synthetic methodologies well-known to those skilled in organic chemistry. A typical synthesis is carried out by reacting a 4-bromo or 4-iodo aniline with a benzoic acid having a leaving group at the 2-position to give a 2-(phenylamino)- benzoic acid. This process is depicted in Scheme 1.
Scheme 1
Figure imgf000035_0001
base
Figure imgf000035_0002
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 CONR6R7, are readily prepared by reacting the foregoing benzoic acids with an amine of the formula HNR6R7. The reaction is carried out by reacting approximately equimolar quantities of the benzoic acid and amine in an unreactive organic solvent in the presence of a coupling reagent. Typical solvents are chloroform, dichloromethane, tetrahydrofuran, benzene, toluene, and xylene. Typical coupling reagents include DCC, EEDQ, PyBrOP, and PyBOP. The reaction is generally complete after about 10 minutes to about 2 hours when carried out at a temperature of about 0°C to about 60°C. The product amide is readily isolated by removing the reaction solvent, for instance by evaporation, and further purification can be accomplished by normal methods such as chromatography, crystallization, or distillation. The hydrazides (z = CONHNR1.3R11) are similarly prepared by coupling a benzoic acid with a hydrazine of the formula H2HNR10R11. The benzyl alcohols of the invention, compounds of Formula I where Z is CH2OR6 and Rβ is hydrogen, are readily prepared by reduction of the corresponding benzoic acid according to the following Scheme 2.
Scheme 2
Figure imgf000037_0001
Typical reducing agents commonly employed include borane in tetrahydrofuran. The reduction normally is carried out in an unreactive organic solvent such as tetrahydrofuran, and generally is complete within about 2 hours to about 24 hours when conducted at a temperature of about 0°C to about 40°C.
The following detailed examples illustrate specific compounds provided by this invention.
EXAMPLE 1 4-Fluoro-2-(4-iodo-2-methylphenylamino benzoic acid To a stirring solution comprised of 3.16 g (0.0133 mol) of 2-amino-5- iodotoluene in 5 mL of tetrahydrofuran at -78°C was added 10 mL (0.020 mol) of a 2.0 M lithium diisopropylamide in tetrahydrofuran heptane/ethenylbenzene (Aldrich) solution. The resulting green suspension was stirred vigorously for 15 minutes, after which time a solution of 1.00 g (0.00632 mol) of 2,4-difluorobenzoic acid in 10 mL of tetrahydrofuran was added. The reaction temperature was allowed to increase slowly to room temperature, at which temperature it was stirred for 2 days. The reaction mixture was concentrated. Aqueous HCl (10%) was added to the concentrate, and the solution was extracted with dichloromethane. The organic phase was dried (MgSO_ι) and then boiled over a steambath to low volume and cooled to room temperature. The off-white fibers were collected by vacuum filtration, rinsed with hexanes, and vacuum-oven dried. (76°C; ca. 10 mm of Hg) to afford 1.10 g (47%) of the desired material; mp 224-229.5°C;
IH 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;
19F NMR (376 MHz; DMSO): δ -104.00 to -104.07 (m); IR (KBr) 1670 (C = O stretch) cm" 1 ;
MS (CI) M+l = 372. Analysis calculated for C14Hι 1FINO2: 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 (MgSO4) 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 C16H16CIIN2O2:
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-phenylaminoVbenzyl 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, 5=1.1 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 C14H13FINO:
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 phenyl] -methanol
Several invention compounds of Formula I were prepared utilizing combinatorial synthetic techniques. The general procedure is as follows:
To a 0.8-mL autosampler vial in a metal block was added 40 μL of a 0.5 M solution of the acid in DMF and 40 μL of the reagent amine (2 M solution in Hunig's base and 1 M in amine in DMF). A 0.5 M solution of PyBrop was freshly prepared and 50 μL were added to the autosampler vial. The reaction was allowed to stand for 24 hours.
The reaction mixture was transferred to a 2-dram vial and diluted with 2 mL of ethyl acetate. The organic layer was washed with 3 mL of distilled water and the water layer washed again with 2 mL of ethyl acetate. The combined organic layers were allowed to evaporate to dryness in an open fume hood. The residue was taken up in 2 mL of 50% acetonitrile in water and injected on a semi-prep reversed phase column (10 mm x 25 cm, 5 μM spherical silica, pore size 115 A derivatized with C-18, the sample was eluted at 4.7 mL/min with a linear ramp to 100% acetonitrile over 8.5 minutes. Elution with 100%) acetonitrile continued for 8 minutes). Fractions were collected by monitoring at 214 nM. The residue was dissolved in chloroform and transferred to a preweighed vial, evaporated, and weighed again to determine the yield.
EXAMPLES 53-206 The following compounds of Formula I were prepared by combinatorial methodology:
Example Compound MS
No. M-H
53 5-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 510 phenylamino)-benzamide
54 N-(2,3-Dihydroxy-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- 462 phenylamino)-benzamide
55 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2- 577 piperidin- 1 -yl-ethyl)-benzamide
56 3,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 432 phenylamino)-benzamide
57 N-(2,3-Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl- 444 phenylamino)-benzamide
58 3,4-Difluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 446 phenylamino)-benzamide
59 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 564 (2-pyrrolidin- 1 -yl-ethyl)-benzamide
60 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 571 (2-pyridin-4-yl-ethyl)-benzamide
61 4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 414 benzamide 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-moφholin-4-yl-ethyl)-benzamide
64 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-moφholin- 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-moφholin-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-moφholin- 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 1 -yl-ethyl)-benzamide
89 5-Chloro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-propyl}- 557* 2-(4-iodo-2-methyl- phenylamino)- benzamide
90 5-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l -yl]-propyl}- 541 * 2-(4-iodo-2-methyl- phenylamino)- benzamide
91 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl methyl- 487 benzamide
92 5-Bromo-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-propyl}- 601* 2-(4-iodo-2-methyl- phenylamino)- benzamide
93 5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- 486* phenylamino)- benzamide Example Compound MS
No. M-H
94 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-l-yl- 497* ethyl)-benzamide
95 (3-Hydroxy-pyrrolidin-l -yl)-[2-(4-iodo-2-methyl-phenylamino)- 466 5-nitro-phenyl]-methanone
96 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-l-yl- 484* ethyl)-benzamide
97 5-Bromo-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- 530* phenylamino)- benzamide
98 N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-chloro-2-(4-iodo- 518* 2-methyl- phenylamino)- benzamide
99 N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-bromo-2-(4-iodo- 562* 2-methyl- phenylamino)- benzamide
100 [5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(3-hydroxy- 499 pyrrolidin- 1 -yl)-methanone
101 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic acid phenethyl 501 ester
102 N-{3-[4-(2-Hydroxy-ethyl)-piperazin-l-yl]-propyl}-2-(4-iodo- 568* 2-methyl-phenylamino)- benzamide
103 [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(3-hydroxy- 455 pyrrolidin- 1 -yl)-methanone
104 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- 460 benzamide
105 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-l-yl- 528* ethyl)-benzamide
106 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-l-yl- 542* ethyl)-benzamide
107 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-l-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
1 14 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl- 556* propyl)-benzamide
115 N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-2-(4-iodo-2-methyl- 529* phenylamino)-5-nitro- benzamide
116 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-moφholin-4-yl- 500* ethyl)-benzamide
117 5-Chloro-N-(3-diethylamino-propyl)-2-(4-iodo-2-methyl- 500* phenylamino)-benzamide
118 5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2 -methyl- 514* phenylamino)-benzamide
1 19 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -piperidin- 1-yl- 512* propyl)-benzamide
120 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin-l-yl- 509* ethyl)-benzamide
121 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin- 1-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-moφholin-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-moφholin-4-yl- 484* ethyl)-benzamide
133 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl- 496* propyl)-benzamide
134 [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- 482 [4-(2-hydroxy-ethyl)-piperazin- 1 -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-sulfarnoyl- 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
M+H
EXAMPLE 207 Preparation of |"4-Chloro-2-(l H-tetrazol-5-ylH4-iodo-2 -methyl -phenyl)-amine
Step a: Preparation of 5-chloro-2-fluoro-benzaldehyde
To a solution of 1 -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: lϊi NMR (CDC1 ): δ, 10.3 (s, -C(=O)H).
Step b: Preparation of 5-chloro-2-fluoro-benzaldehyde oxime
A solution of 5-chloro-2-fluoro-benzaldehyde (10 g, 0.0631 mol), hydroxylamine hydrochloride (6.57 g, 0.0946 mol) and pyridine (8.3 mL, 0.1010 mol) in EtOH (100 mL) was heated at 75°C (oil bath temperature) for 1 hour and the solvent removed under vacuum to give an oil. The oil was partitioned between water and CH2CI2. The CH2CI2 layer was dried (MgSO4) and the solvent removed under vacuum to give crude aldoxime as a solid. The solid was purified by medium pressure liquid chromatography on silica. Elution with CH2Cl2 gave 4.87 g (28%) of the aldoxime as white solid: mp 95-97°C; Analysis calculated for C7H5NOFCI:
C, 48.44; H, 2.90; N, 8.07. Found: C, 48.55; H, 2.69, N, 7.90.
Step c: Preparation of 5-chloro-2-fluoro-benzonirile
A solution of the 5-chloro-2-fluoro-benzaldehyde oxime (3.15 g, 0.0182 mol) in acetic anhydride (150 mL) was refluxed for 16 hours. The reaction mixture was cooled to room temperature and poured into saturated aqueous NaHCO3 (200 mL) solution. The mixture was extracted with Et2θ. The Et2θ layer was dried (K2CO3) and the solvent removed to give the product as an oily solid. The product was used without further purification in the next step.
Step d: Preparation of 5-(5-chloro-2-fluoro-phenyl -lH-tetrazole
A mixture of 5-chloro-2-fluoro-benzonitrile (2.84 g, 0.01823 mol), butanol (15 mL), sodium azide (1.543 g, 0.0237 mol), acetic acid (1.36 mL, 0.0237 mol) was refluxed for 24 hours. The reaction mixture was cooled to room temperature, additional 1.543 g sodium azide added, and the reaction mixture refluxed for additional 24 hours. After cooling to room temperature, Et2θ (100 mL) and 10%) aqueous NaOH (200 mL) were added sequentially. The mixture was vigorously stirred. The aqueous layer was separated, cooled with ice-methanol bath (-15°C) and acidified to pH 1 with cone. HCl. A gray solid precipitated. The solid was dried in vacuum at 50°C to give 1.76 g (49%) of 5-(5-chloro-2-fluoro-phenyl)-lH- tetrazole: mp partial melt at 110°C, complete melting at 124°C);
*H (400 Mz, CDCI3): δ 8.19-8.08 (m, IH), 7.77-7.71 (m, IH), 7.61-7.52 (m, IH);
13C (100 Mz, CDCI3): δ 159.00, 156.49, 140.88, 133.02, 132.93, 130.73, 129.23,
129.21, 129.08, 126.05, 118.96, 118.73, 114.50; MS (CI) M+l = 199 (100), M = 198 (6). Step e: Preparation of |~4-Chloro-2-( 1 H-tetrazol-5-yl (4-iodo-2-methyl-phenyl)- amine
To a solution of 2-methyl-4-iodoaniline (3.52 g, 0.0151 mol) in THF (25 mL) at -78°C, LDA (2 molar solution in THF, 11.33 mL, 0.02267 mol) was added dropwise. After stirring for 0.5 hours, a solution of l-(tetrazol-5-yl)-2- fluoro-5-chlorobenzene (1.5 g, 0.00756 mol) in THF (15 mL) was added dropwise. The reaction was stirred for 16 hours as it warmed up to room temperature. The reaction mixture was quenched with aqueous cone. NH4CI solution and extracted with CH2CI2. The organic layer was dried (MgSO4) and the solvent removed giving a crude product as an oil. The oil with CH2CI2-
>CH2Cl2:MeOH (9.7:0.3) gave 1.5 g (48%) of the desired product: mp 205-208°C; lH (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+l = 412 (85),
M = 411 (100). Analysis calculated for C14H1 ιN5ClI-0.5H2θ:
C, 39.97; H, 2.87; N, 16.65. Found: C, 38.87, H, 2.77; N, 16.47.
The following tetrazole substituted phenylamines were prepared by following the general procedure of Example 207.
EXAMPLE 208 (4-iodo-2-methyl-phenyl -r2-(lH-tetrazol-5-vπ-phenyl]amine, mp 231°C (dec)
EXAMPLE 209 r4-nitro-2-riH-tetrazol-5-yl -(4-iodo-2-methyl-phenyl)-amine, mτ> 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
Figure imgf000058_0001
base
Figure imgf000058_0002
R6a HN-O— R 7, a
Figure imgf000058_0003
The phenylamino benzoic acid next is reacted with a hydroxylamine derivative HNR6aOR7a in the presence of a peptide coupling reagent.
Hydroxylamine derivatives that can be employed include methoxylamine, N-ethyl-isopropoxy amine, and tetrahydro-oxazine. Typical coupling reagents include 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline (EEDQ), 1 ,3-dicyclohexylcarbodiimide (DCC), bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP) and (benzotriazolyloxy)tripyrrolidino phosphonium hexafluorophosphate (PyBOP). The phenylamino benzoic acid and hydroxylamino derivative normally are mixed in approximately equimolar quantities in an unreactive organic solvent such as dichloromethane, tetrahydrofuran, chloroform, or xylene, and an equimolar quantity of the coupling reagent is added. A base such as triethylamine or diisopropylethylamine can be added to act as an acid scavenger if desired. The coupling reaction generally is complete after about 10 minutes to 2 hours, and the product is readily isolated by removing the reaction solvent, for instance by evaporation under reduced pressure, and purifying the product by standard methods such as chromatography or crystallizations from solvents such as acetone, diethyl ether, or ethanol.
An alternative method for making the invention compounds involves first converting a benzoic acid to a hydroxamic acid derivative, and then reacting the hydroxamic acid derivative with an aniline. This synthetic sequence is depicted in Scheme 4, 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
Figure imgf000060_0001
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
Figure imgf000061_0001
base
Figure imgf000061_0002
The synthesis of compounds of Formula (II) is further illustrated by the following detailed examples.
EXAMPLE la
4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylaminoVbenzamide
(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%)) 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,
Figure imgf000062_0001
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 stretctycm"1; MS (CI) M+l = 372.
Analysis calculated for C^Hj 1FINO2:
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;
*H 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,
Figure imgf000063_0001
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+l = 387. Analysis calculated for C14H12FIN2O2: C, 43.54; H, 3.13; N, 7.25.
Found: C, 43.62; H, 3.24; N, 6.98.
EXAMPLE 2a 5-Bromo-3,4-difluoro-N-hvdroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide (a) Preparation of 5-Bromo-2 .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; lϋ NMR (400 MHz, DMSO): δ 13.97 (broad s, IH, 8.00-7.96 (m, IH);
13C NMR (100 MHz, DMSO): δ 162.96, 129.34, 118.47, 104.54 (d, JC-F=22.9 Hz);
19F NMR (376 MHz, DMSO): δ -120.20 to -120.31 (m), -131.75 to -131.86 (m), -154.95 to -155.07 (m);
IR (KBr) 1696 (C=O stretch^m"1; MS (CI) M+l = 255. Analysis calculated for C74H21 BrF3U2:
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 st red 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 stined 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;
*H NMR (400 MHz, DMSO): δ 9.03 (s, IH), 7.99 (dd, IH, J=7.5, 1.9 Hz), 7.57 (dd, IH, J=1.5 Hz), 7.42 (dd, IH, J=8.4, 1.9 Hz), 6.70 (dd, IH, J=8.4,
6.0 Hz), 2.24 (s, 3H);
19F NMR (376 MHz, DMSO): δ -123.40 to -123.47 (m); -139.00 to -139.14 (m);
IR (KBr) 1667 (C=O stretch^m'1; MS (CI) M+l = 469. Analysis calculated for C \ 4H9BrF2lNO2 :
C, 35.93; H, 1.94; N, 2.99; Br, 17.07; F, 8.12; I, 27.11. Found: C, 36.15; H, 1.91; N, 2.70; Br, 16.40; F, 8.46; I, 26.05. (c) Preparation of 5-Bromo-3,4-difluoro-N-hvdroxy-2-(4-iodo-2-methyl- phenylamino)-benzamide To a stirred solution comprised of 5-bromo-3,4-difluoro-2-(4-iodo-
2-methyl-phenylamino)-benzoic acid (0.51 g, 0.0011 mol), O-(tetrahydro-2H- pyran-2-yl)-hydroxylamine (0.15 g, 0.0013 mol), and diisopropylethylamine (0.25 mL, 0.0014 mol) in 20 mL of an equivolume tetrahydrofuran- dichloromethane solution was added 0.6794 g (0.001306 mol) of solid PyBOP (Advanced ChemTech) directly. The reaction mixture was stirred at 24°C for
10 minutes, and then was concentrated to dryness in vacuo. The concentrate was suspended in 100 mL of 10% aqueous hydrochloric acid. The suspension was extracted with 125 mL of diethyl ether. The ether layer was separated, washed with 75 mL of 10%) aqueous sodium hydroxide, and then with 100 mL of dilute acid. The ether solution was dried (MgSO4) and concentrated in vacuo to afford
0.62 g (100%)) of an off-white foam. The foam was dissolved in ca. 15 mL of methanolic hydrogen chloride. After 5 minutes, the solution was concentrated in vacuo to an oil, and the oil was purified by flash silica chromatography. Elution with dichloromethane: dichloromethane-methanol (99:1) afforded 0.2233 g (42%) of a yellow powder. The powder was dissolved in diethyl ether and washed with dilute hydrochloric acid. The organic phase was dried (MgSO4) and concentrated in vacuo to afford 0.200 g of a foam. This product was triturated with pentane to afford 0.1525 g of a powder that was repurified by flash silica chromatography. Elution with dichloromethane afforded 0.0783 g (15%) of an analytically pure title compound, mp 80-90°C; iH NMR (400 MHz, DMSO): δ 11.53 (s, IH), 9.38 (s, IH), 8.82 (s, IH), 7.70 (dd,
IH, J=7.0, 1.9 Hz), 7.53 (s, IH), 7.37 (dd, IH, J=8.4, 1.9 Hz), 6.55 (dd, IH, J=8.2, 6.5 Hz), 2.22 (s, 3H);
19F NMR (376 MHz, DMSO): δ -126.24 to -126.29 (m), -137.71 to -137.77 (m);
IR (KBr) 3346 (broad, O-H stretch), 1651 (C=O stretch)cm-!; MS (CI) M+l = 484.
Analysis calculated for C14H106^2^202 :
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., (NHRga )-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-Difiuoro-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-i sopropoxy-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-ρhenylamino)-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 167-169 °C
Η-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
1H-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)
PD298127
mp 127-135 °C
5 -chloro-N-cyclopropyl methoxy-3,4-difluoro-2-[4-iodo-2 -methyl phenylaminojbenzamide
Proton 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 MEK inhibitors described above to prevent and treat asthma has been demonstrated in three different assays: (1) inhibition of antigen-induced interleukin-5 (IL-5) production in vitro, (2) inhibition of the passive-transfer of eosinophilic lung inflammation in vivo, and (3) inhibition of active eosinophilic lung inflammation in vivo. For each of these assays, female C57BL/6 mice obtained from the Jackson Laboratory (Bar Harbor, ME) were given an intraperitoneal (i.p.) injection of ovalbumin (OVA, Grade V, Sigma Chemical Company, St. Louis, MO) adsorbed to aluminum hydroxide (10 μg ON A + 9 mg aluminum hydroxide in 200 μL saline). This sensitizes OVA-specific lymphocytes for subsequent restimulation either in vivo or in vitro.
The first set of experiments was designed to determine whether the MEK inhibitors could prevent antigen-induced production of IL-5 by the ONA-primed splenocytes in vitro. IL-5 is required for the differentiation, migration, and survival of pulmonary eosinophils, which are thought to be responsible for much of the pathology associated with human asthma. In order to examine the effects of MEK inhibitors on IL-5 production, ONA-sensitized mice were sacrificed by cervical dislocation 14 days after sensitization (Day 14), the spleens were excised and disaggregated, and the erythrocytes were lysed. The splenocytes were washed and resuspended at 5 x 10 > cells/mL in complete medium consisting of
RPMI 1640 (Gibco BRL, Gaithersburg, MD) with 10% heat-inactivated fetal calf serum (Hyclone, Logan, UT), 55 μM 2-mercaptoethanol, 50 U/mL penicillin G, 50 μg/mL streptomycin sulfate, and 2 mM L-glutamine (Gibco BRL). The splenocytes were then cultured at 37°C in the presence of 200 μg/mL ON A. MEK inhibitors were also added to the cultures from sterile 10 mM stock solutions (in
DMSO). After 3 days, the culture medium was recovered and assayed for IL-5 by specific ELISA. The results of the analysis of IL-5 inhibition are presented in Table 1. All MEK inhibitors tested were found to potently inhibit antigen-induced IL-5 production. Table 1. The Effects of MEK Inhibitors on Antigen- Induced IL-5 Production
MEK Inhibitor IC50 (nM)
PD 184386 23
PD 171984 117
PD 170611 1,121
PD 184161 1,147
PD 177168 1,205
PD 184352 1,622
PD 098059 17,440
When OVA-sensitized spleen cells are restimulated with OVA in vitro for 3 days, as described above, the spleen cells not only produce IL-5, but also acquire the ability to induce eosinophilic lung inflammation when transfened into naϊve recipient mice. The critical cell type responsible for this adoptively- transferred activity is thought to be IL-5 -producing T lymphocytes. Because the results of the first set of experiments indicated that the MEK inhibitors inhibited IL-5 production by cultured splenocytes, a second set of experiments was initiated to determine whether the MEK inhibitor-treated cells were capable of transferring eosinophilic lung inflammation to naϊve mice. Splenocytes from OVA restimulation cultures, with or without the addition of MEK inhibitors were harvested after 3 days of culture, washed three times, and resuspended at
1 x 10 > cells/mL in sterile saline. Groups of five naϊve (unsensitized) C57BL/c mice were injected i.p. with 200 μL of the cell suspension (2 x 10^ cells). Three days after transfer of cells, the recipient mice were challenged with a 12-minute inhalation of an aerosol formulation of 1.5% OVA in saline (weight/volume), the mist being produced by a nebulizer (small particle generator model SPAG-2, ICN Pharmaceuticals, Costa Mesa, CA). Three days after aerosol challenge, the mice were anesthetized with an i.p. injection of an anesthetic mixture comprising Ketamine, acepromazine, and xylazine. The trachea of each mouse was exposed and cannulated. The lungs and upper airways were lavaged with 0.5 mL of cold
(5°C) phosphate buffered saline (PBS). The cells within a 200 μL portion of the bronchoalveolar lavage (BAL) fluid were enumerated using a Coulter counter (Model ZB 1, Coulter Electronics, Hialeah, FL). The remaining BAL fluid was then centrifuged at 300 x g for 5 minutes, and the cells resuspended in 1 mL of Hank's balanced salt solution (HBSS, Gibco BRL), containing 0.5% fetal calf serum, and 10 mM of N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid
(HEPES, Gibco BRL). The cell suspension (100 μL) was centrifuged in a cytospin (Shandon Southern Instruments, Sewickley, PA) and stained with Diff Quick to distinguish neutrophil, eosinophil, monocyte, and lymphocyte subsets. The number of eosinophils in the BAL fluid was determined by multiplying the percentage of eosinophils by the total cell count.
As shown in Table 2, OVA-sensitized splenocytes cultured in the absence of MEK inhibitor, when transfened to naϊve recipient mice, were able to promote eosinophilic lung inflammation in response to an aerosol challenge with OVA. In contrast, splenocytes cultured in the presence of the MEK inhibitors PD 171984, PD 184352, and PD 184386 (10 μM each) did not promote eosinophilic lung inflammation (>99% inhibition). For each of the MEK inhibitors used, a 10 μM concentration was previously found to inhibit IL-5 production by over 75% (Table 1). These results suggest that the MEK inhibitors inhibit the IL-5-producing T lymphocytes that are required to support asthma-like eosinophilic lung inflammation in mice.
Table 2. The Effects of MEK Inhibitors on the Adoptive-Transfer of Eosinophilic Lung Inflammation
Treatment of Spleen Cell Culture % Inhibition of BAL Eosinophils
Compound Dose (μM)
None 0
PD 171984 10 99.82
PD 184386 10 99.78
PD 184352 10 99.46
The final set of experiments was designed to test whether MEK inhibitors could inhibit active OVA-induced eosinophilic lung inflammation in mice. Mice were sensitized with OV A/aluminum hydroxide on Day 0 as described above. On Day 14, the mice were challenged by aerosol with 1.5% OVA, as described above for the adoptive-transfer recipients. One group of eight sensitized mice was dosed orally with vehicle (0.5% hydroxypropylmethylcellulose/0.25% TWEEN-80). Other groups of sensitized mice (8 mice per group) were given oral doses of a
MEK inhibitor. The test compound was dissolved in the vehicle, and the volume for each dosage was adjusted to 200 μL, so that each test animal received the same oral volume. In experiments reported in Table 3 and Table 4, the MEK inhibitor was administered starting on Day 13 (ie, 13 days after initial sensitization and 1 day prior to aerosol challenge), and continued daily through Day 16 (4 days total). In experiments reported in Table 5, the MEK inhibitor was administered starting on Day 7 (ie, 7 days after initial sensitization and 7 days prior to aerosol challenge), and continued daily through Day 16 (9 days total). On Day 17 of each experiment (17 days following the initial OVA challenge, and 3 days after the OVA aerosol challenge), all animals including controls were anesthetized, cannulated, and lavaged as previously described. The number of BAL eosinophils was determined as described above.
In the initial analysis of active OVA-induced lung inflammation, multiple MEK inhibitors (PD 171984, PD 177168, PD 184161, PD 184386, and PD 184352) were dosed orally for 4 days. Only one compound, PD 171984, demonstrated any inhibition of pulmonary eosinophilia (Table 3). PD 171984, along with PD 184352, were tested again at multiple doses, again dosing for only 4 days. The results in Table 4 essentially parallel those in Table 3 for these compounds; PD 171984 appears active, whereas PD 184352 does not. As reported in Table 5, increasing the oral dosing schedule from 4 days to 9 days (7 days prior to aerosol challenge, 2 days after) resulted in a degree of inhibitory activity for PD 184352 at 100 mg/kg (59.85% inhibition, p = 0.11). PD 171984 continued to demonstrate statistically significant inhibitory activity under this dosing regimen. In total, these results indicate that MEK inhibitors, when used in vitro, are potent inhibitors of IL-5 production, and completely inhibit the ability of antigen- stimulated cells to adoptively transfer asthma-like symptoms to naϊve recipient mice. When used in vivo, some MEK inhibitors are more active than others. However, a less potent compound (PD 184352) was shown to inhibit the asthmalike response in mice under a more rigorous dosing regimen. Thus, the foregoing data establish that the selective MEK inhibitors are active in inhibiting a model of asthma in mice. The compounds have little or no toxic effects, and accordingly are particularly well-suited for treating and controlling asthma in children, 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 antiasthmatic effective dose, which is that amount that is effective to treat the particular asthma severity for which treatment is needed or otherwise desired.
Table 3. The Effect of MEK Inhibitors on Eosinophilic Lung Inflammation in Mice
MEK Inhibitor Dose (μM) %> Inhibition of BAL Eosinophilia
___
PD 171984 100
PD 177168 100 -123.38
PD 184161 100 -32.53
PD 184386 100 -33.24
PD 184352 150 -5.41 * ρ = 0.08
Table 4. Inhibition of BAL Eosinophils With 4-Day Compound Dosing
Dose (mg/kg) % Inhibition of BAL Eosinophils by:
PD 184352 PD 171984
0 0 0
10 -22.7 38.4*
30 -153.8 46.6*
100 -8.2 58.4*
* Significantly different from control (p <0.05) Table 5. Inhibition of BAL Eosinophils With 9-Day Compound Dosing
Dose (m ig/kg) % Inhibition of BAL Eosinophils by:
PD 184352 PD 171984
Experiment 1 Experiment 2
0 0 0 0
10 -42.99 -13.74 50.15*
30 1.83 80.64* 37.23*
100 59.85 88.40* 54.77*
* Significantly different from control (p <0.05)
The foregoing data establish that the selective MEK inhibitors are active in both inhibiting and controlling the asthmatic disease, for example, prior to actual challenge and following challenge. The compounds are therefore useful in the prophylaxis of asthma, and also in treating and alleviating the symptoms that accompany the disease during its active stage. The compounds have little or no toxic effects, and accordingly are particularly well-suited for treating and controlling asthma in children, 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 antiasthmatic effective dose, which is that amount that is effective to treat the particular asthma severity for which treatment is needed or otherwise desired. 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 or treating asthma in patients, said method comprising the step of administering an antiasthmatic-effective amount of a MEK inhibitor to a patient in need of treatment, or to a patient suspected of developing asthma and in need of prophylactic treatment.
A method according to claim 1 wherein the patient being treated has been diagnosed as having asthma and is in need of treatment.
A method according to claim 1 , wherein the MEK inhibitor is a selective MEK inhibitor.
A method for preventing or treating asthma in patients, said method comprising the step of administering to a patient in need of treatment, or to a patient suspected of developing asthma and in need of prophylactic treatment, an antiasthmatic effective amount of a phenyl amine compound of Formula I:
Figure imgf000084_0001
wherein:
R\ is hydrogen, hydroxy, C -Cg alkyl, Cj-Cg alkoxy, halo, trifluoromethyl, or CN; R2 is hydrogen;
R3, R4, and R5 independently are hydrogen, hydroxy, halo, trifluoromethyl, Cj-Cg alkyl, Cj-Cg alkoxy, nitro, CN, or -(O or NH)m-(CH2)n-R9> where R9 is hydrogen, hydroxy, COOH, orNRioRn; n is 0-4; m is 0 or 1 ; RJ O and R\ independently are hydrogen or Cj-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3-10 member cyclic ring optionally containing 1, 2, or
3 additional heteroatoms selected from O, S, NH, or N-Cj-Cg alkyl; Z is COOR7, tetrazolyl, CONR6R7, CONHNR10Rι 1 , or CH2OR7;
Rg and R7 independently are hydrogen, Cj-Cg alkyl, C2-C alkenyl,
C2-Cg alkynyl, (CO)-C]-Cg alkyl, aryl, heteroaryl, 3-C10 cycloalkyl, or C3-CJ0 (cycloalkyl optionally containing 1,
2, or 3 heteroatoms selected from O, S, NH, or N alkyl); or R and R7 together with the nitrogen to which they are attached complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl; and wherein 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, CpC4 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 a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
5. The method of claim 4, wherein the MEK inhibitor is a compound of Formula (I) wherein (a) Ri is hydrogen, methyl, methoxy, fluoro, chloro, or bromo; (b) R2 is hydrogen; (c) R3, R4, and R5 independently are hydrogen, fluoro, chloro, bromo, iodo, methyl, methoxy, or nitro; (d) R10 and R} 1 independently are hydrogen or methyl; (e) Z is COOR7, tetrazolyl, CONRόR?, CONHNRioRi 1 , or CH2OR7; Re and R7 independently are hydrogen, C \→\ alkyl, heteroaryl, or C 3-5 cycloalkyl optionally containing one or two heteroatoms selected from O, S, or NH; or R and R7 together with the nitrogen to which they are attached complete a 5-6 member cyclic ring optionally containing 1 or 2 additional heteroatoms selected from O, NH or N-alkyl; and wherein any of the foregoing alkyl or aryl groups can be unsubstituted or substituted by halo, hydroxy, methoxy, ethoxy, or heteroaryloxy; (f) Z is COOR7; (g) R7 is H, pentafluorophenyl, or tetrazolyl; (h) R3, R-j, and R5 are independently H, fluoro, or chloro; (i) R4 is fluoro; (j) two of R3, R4, and R5 are fluoro; or (k) or combinations of the above.
6. The method of claim 5, wherein the MEK inhibitor is a compound of Formula (I) wherein: Z is COOR7; R7 is H, pentafluorophenyl, or tetrazolyl; R3 and R5 are independently H, fluoro, or chloro; and R-j is fluoro.
7. The method of claim 4 wherein the phenyl amine is selected from:
[4-Chloro-2-(lH-tetrazol-5-yl)-phenyl(4-iodo-2-methyl-phenyl)- amine;
(4-Iodo-2-methyl-phenyl)-[2-(lH-tetrazol-5-yl)-phenyl]amine;
[4-Nitro-2-(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-phenylarnino)-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 -y 1] -propyl } - 2-(4-iodo-2-methyl-phenylamino)-benzamide;
N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; N-Butyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-N,N-diethyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl- benzamide; 5-Bromo-3 ,4-difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
N-(2,3 -Dihydroxy-propyl)-3 ,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2 -piperidin- 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-pynolidin- 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-l-yl- propyl)-benzamide; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -piperidin-
1 -yl-propyl)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thiophen-2-yl- ethyl)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2 -pyrrolidin- 1 -yl- ethyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-morpholin- 4-yl-ethyl)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- pyridin-4-ylmethyl-benzamide; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-
4-ylmethyl-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-N-(3-dimethylamino- propyl)-3 ,4-difluoro-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- ethyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyridin- 4-yl-ethyl)-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(3-hydroxy- propyl)-benzamide ;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyrrolidin- 1 -yl-ethyl)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyl- benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-thiophen- 2-yl-ethyl)-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-N-pyridin-
4-ylmethyl-benzamide;
2-(4-Bromo-2-methyl-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- 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-pynolidin- 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-l-yl]-propyl}-2-(4-iodo- 2-methyl-phenylamino)-benzamide;
5 -Fluoro-2 -(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide; 5-Bromo-2-(4-iodo-2-ethyl-phenylamino)-N-(2 -pyrrolidin- 1 -yl- ethyl)-benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- 1 -yl- ethyl)-benzamide ;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2 -pyrrolidin- 1 -yl- ethyl)-benzamide;
5-Chloro-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-fluoro-2-(4-iodo- 2-methyl-phenylamino)-benzamide; 5-Chloro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-N-(3-diethylamino-2-hydroxy-propyl)-2-(4-iodo- 2-methyl-phenylamino)-benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- 1 -yl- ethyl)-benzamide;
5-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 1 -yl- propyl)-benzamide; N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-2-(4-iodo-2-methyl- phenylamino)-5-nitro-benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- ethyl)-benzamide;
5-Chloro-N-(3-diethylamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5 -Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -piperidin- 1 -yl- propyl)-benzamide;
2-(4-Iodo-2 -methyl -phenylamino)-5-nitro-N-(2 -piperidin- 1-yl- ethyl)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin- 1 -yl- ethyl)-benzamide;
N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
5-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-(3-Diethylamino-propyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
N-(3-Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- 5 -nitro-benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- ethyl)-benzamide;
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin-l-yl- propyl)-benzamide;
[5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(3-hydroxy- pynolidin- 1 -yl)-methanone 5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- ethyl)-benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -piperidin- 1 -yl- propyl)-benzamide;
[5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- [4-(2-hydroxy-ethyl)-piperazin- 1 -yl] -methanone; N-(3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo- 2-methyl-phenylamino)-benzamide;
N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide; 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-(2-Hydroxy-ethyl)-2-(4-iodo-2-ethyl-phenylamino)-5-nitro- benzamide;
2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- benzamide;
5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide;
N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide;
N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide;
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide;
N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide;
N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Allyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide;
2-(4-Iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-5-nitro- benzamide; 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide; 5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide;
N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide;
N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohol;
[5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol; [2-(4-Iodo-2-methyl-phenylamino)-5-nitro-phenyl]-methanol;
[5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol; and
N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide.
8. A method for preventing or treating asthma in patients, said method comprising the step of administering to a patient in need of treatment, or to a patient suspected of developing asthma and in need of prophylactic treatment, an antiasthmatic effective amount of a phenyl amine compound of Formula II:
Figure imgf000097_0001
wherein:
Rja is hydrogen, hydroxy, Cj-Cg alkyl, Cj-Cg alkoxy, halo, trifluoromethyl, or CN;
R2a *s hydrogen;
R3a, R4a, and R5a independently are hydrogen, hydroxy, halo, trifluoromethyl, Cj-Cg alkyl, Cj-Cg alkoxy, nitro, CN, or
(O or NH)m-(CH2)n-R9a' where R9a is hydrogen, hydroxy, CO2H or NR10aRl la- n is 0-4; m is 0 or 1;
RlOa and Rl la independently are hydrogen or Cj-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3- to 10-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S, NH, or N-C!-Cg alkyl;
Rβa is hydrogen, Cj-Cg alkyl, (CO)-Cj-Cg alkyl, aryl, aralkyl, or
C3-C10 cycloalkyl; R7a is hydrogen, Cj-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl,
C3-C10 (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NR93); and wherein 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, d-C4 alkylamino, di(C1-C4)alkylamino, C3- cycloalkyl, phenyl, phenoxy, C3-C5 heteroaryl or heterocyclic radical, or C3-C5 heteroaryloxy or heterocyclic radical-oxy; or Rga and R7a taken together with the N to which they are attached can complete a 5- to 10-membered cyclic ring, optionally containing one, two, or three additional heteroatoms selected from O, S, or NRj QaRl 1 →\ or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
9. The method of claim 8, wherein the phenyl amine has a structure of Formula (II) wherein Rla is methyl, fluoro, or chloro; R2a is H; R3a, R-ia, and R5aare each H or F; Rόa is H; R a is methyl, ethyl, 2-propenyl, propyl, butyl, pentyl, hexyl, cyclopropylmethyl, cyclobutyl methyl, cyclopropylmethyl, or cyclopropylethyl; and 4' position is I.
10. The method of claim 8, comprising a MEK inhibitor having a structure of Formula (II) wherein: ^ is F at the 4 position, para to the CO-N-Rδa-OR- 3 group and meta to the bridging nitrogen; at least one of
R3a and R a is F or Cl; and Rla is methyl or chloro.
11. The method of claim 8, wherein the phenyl amine has a structure 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-phenylarnino)-N- (isopropoxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-but-
3 -ynyloxy)-benzamide;
5-Chloro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydro-pyran- 2-yloxy)-benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy- benzamide;
4-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide;
5-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydropyran-
2-yloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (3-phenylprop-2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (3-furylmethoxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (2-thienylmethoxy)-benzamide ;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but- 3-ynyloxy)-benzamide; 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-methyl- prop-2-enyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but- 2-enyloxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(methoxy)- benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(ethoxy)- benzamide; 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-
(cyclobutoxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(isopropoxy)- benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (2-phenoxyethoxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclopropyl- methoxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(n-propoxy)- benzamide; 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-( 1 -methyl- prop-2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3-(3- fluorophenyl)-prop-2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(4,4- dimethylpent-2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (cyclopentoxy)-benzamide;
3,4,5-Trifluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5 -Chloro-3 ,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N- hydroxy-benzamide ;
N-Hydroxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzamide; 3,4,5-Trifluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy- benzamide;
5-Chloro-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N- hydroxy-benzamide; 5 -Bromo-2-(2-chloro-4-iodo-phenylamino)-3 ,4-difluoro-N- hydroxy-benzamide;
2-(2-Fluoro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide;
2-(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy- benzamide;
5 -Chloro-2-(2-chloro-4-iodo-phenylamino)-3 ,4-difluoro-N- hydroxy-benzamide;
5 -Bromo-2-(2-bromo-4-iodo-phenylamino)-3 ,4-difluoro-N- hydroxy-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-methyl- benzamide;
2-(2-Bromo-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy- benzamide;
2-(2-Bromo-4-iodo-phenylamino)-5-chloro-3,4-difmoro-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-mtro- 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.
12. The method of preventing or treating asthma in a mammal comprising administering to the patient in need of treatment or suspected of developing asthma and in need of prophylactic treatment an antiasthmatic effective dose of the MEK inhibitor 2-(2-chloro-4-iodophenylamino)-N- cycloproplymethoxy-3 ,4-difluorobenzamide.
13. The method of preventing or treating asthma in a mammal comprising administering to the patient in need of treatment or suspected of developing asthma and in need of prophylactic treatment an antiasthmatic effective dose of the MEK inhibitor 2-(2 -methyl -4-iodophenylamino)-N- hydroxy-3,4-difluoro-5-bromobenzamide.
14. The method of preventing or treating asthma in a mammal comprising administering to the patient in need of treatment or suspected of developing asthma and in need of prophylactic treatment an antiasthmatic effective dose of a compound selected from: 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-
3,4-difluorobenzamide (PD 184352);
2-(2-Methyl-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD 170611);
2-(2-Methyl-4-iodophenylamino)-N-hydroxy-3,4-difluoro- 5-bromobenzamide (PD 171984);
2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy- 3,4-difluoro-5-bromobenzamide (PD 177168);
2-(2-Methyl-4-iodophenylamino)-N-cyclobutylmethoxy- 3,4-difluoro-5-bromobenzamide (PD 180841); 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-
3,4-difluoro-5-bromobenzamide (PD 184161);
2-(2-Chloro-4-iodophenylamino)-N-hydroxy-3,4-difluoro- 5-bromobenzamide (PD 184386);
2-(2-Chloro-4-iodophenylamino)-N-cyclobutylmethoxy- 3 ,4-difluorobenzamide (PD 185625); 2-(2-Chloro-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD 185848);
2-(2-Methyl-4-iodophenylamino)-N-hydroxy- 3,4-difluorobenzamide(PD 188563); 2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy-
3,4,5-trifluorobenzamide (PD 198306); and
2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy- 4-fluorobenzamide (PD 203311).
15. The method of preventing or treating asthma in a mammal comprising administering to the patient in need of treatment or suspected of developing asthma and in need of prophylactic treatment an antiasthmatic effective dose of a compound:
2-(2-chloro-4-iodophenylamino)-5-chloro-N-cyclopropylmethoxy -3,4- difluorobenzamide (PD 297189), 2-(4-iodophenylamino)-N- cyclopropylmethoxy-5-chloro-3 ,4-difluorobenzamide (PD297190), 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).
16. The method of preventing or treating asthma in a mammal comprising administering to the patient in need of treatment or suspected of developing asthma and in need of prophylactic treatment an antiasthmatic effective dose of a compound which is 2-(2-amino-3-methoxyphenyl)- 4-oxo-4H-[l]benzopyran or 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-
3 ,4-difluoro-5-bromobenzamide (PD 171984).
PCT/US1999/030419 1999-01-07 1999-12-21 Treatment of asthma with mek inhibitors WO2000040235A2 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US09/889,091 US6696440B1 (en) 1999-01-07 1999-12-21 Treatment of asthma with MEK inhibitors
JP2000591992A JP2002534380A (en) 1999-01-07 1999-12-21 Treatment of asthma with MEK inhibitors
AT99968153T ATE292462T1 (en) 1999-01-07 1999-12-21 TREATMENT OF ASTHMA USING MEK INHIBITORS
EP99968153A EP1140062B1 (en) 1999-01-07 1999-12-21 Treatment of asthma with mek inhibitors
CA002350234A CA2350234A1 (en) 1999-01-07 1999-12-21 Treatment of asthma with mek inhibitors
BR9916785-9A BR9916785A (en) 1999-01-07 1999-12-21 Treatment of asthma with mek inhibitors
AU24830/00A AU2483000A (en) 1999-01-07 1999-12-21 Treatment of asthma with mek inhibitors
DE69924641T DE69924641D1 (en) 1999-01-07 1999-12-21 TREATMENT OF ASTHMA ON THE BASIS OF MEK INHIBITORS

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11508699P 1999-01-07 1999-01-07
US60/115,086 1999-01-07

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US09/889,091 A-371-Of-International US6696440B1 (en) 1999-01-07 1999-12-21 Treatment of asthma with MEK inhibitors
US10/753,170 Division US20040141924A1 (en) 1999-01-07 2004-01-07 Treatment of asthma with MEK inhibitors

Publications (2)

Publication Number Publication Date
WO2000040235A2 true WO2000040235A2 (en) 2000-07-13
WO2000040235A3 WO2000040235A3 (en) 2000-11-09

Family

ID=22359251

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/030419 WO2000040235A2 (en) 1999-01-07 1999-12-21 Treatment of asthma with mek inhibitors

Country Status (9)

Country Link
US (2) US6696440B1 (en)
EP (1) EP1140062B1 (en)
JP (1) JP2002534380A (en)
AT (1) ATE292462T1 (en)
AU (1) AU2483000A (en)
BR (1) BR9916785A (en)
CA (1) CA2350234A1 (en)
DE (1) DE69924641D1 (en)
WO (1) WO2000040235A2 (en)

Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1255544A1 (en) * 2000-01-31 2002-11-13 Magainin Pharmaceuticals, Inc. Mucin synthesis inhibitors
EP1262176A1 (en) * 2001-05-09 2002-12-04 Warner-Lambert Company Method of treating or inhibiting neutrophil chemotaxis by administering a mek inhibitor
WO2005054179A3 (en) * 2003-12-03 2005-08-04 Leo Pharma As Hydroxamic acid esters and pharmaceutical use thereof
US6960614B2 (en) 2000-07-19 2005-11-01 Warner-Lambert Company Oxygenated esters of 4-lodo phenylamino benzhydroxamic acids
US7060856B2 (en) 2003-10-21 2006-06-13 Warner-Lambert Company Polymorphic form of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide
US7132546B2 (en) 2000-12-22 2006-11-07 Ishihara Sangyo Kaisha, Ltd. Aniline derivatives or salts thereof and cytokine production inhibitors containing the same
WO2007049820A1 (en) 2005-10-28 2007-05-03 Takeda Pharmaceutical Company Limited Heterocyclic amide compound and use thereof
US7230099B2 (en) 2003-09-03 2007-06-12 Array Biopharma, Inc. Heterocyclic inhibitors of MEK and methods of use thereof
US7235537B2 (en) 2002-03-13 2007-06-26 Array Biopharma, Inc. N3 alkylated benzimidazole derivatives as MEK inhibitors
US7345051B2 (en) 2000-01-31 2008-03-18 Genaera Corporation Mucin synthesis inhibitors
US7378423B2 (en) 2004-06-11 2008-05-27 Japan Tobacco Inc. Pyrimidine compound and medical use thereof
US7425637B2 (en) 2002-03-13 2008-09-16 Array Biopharma Inc. N3 alkylated benzimidazole derivatives as MEK inhibitors
US7485643B2 (en) 2003-11-19 2009-02-03 Array Biopharma Inc. Bicyclic inhibitors of MEK and methods of use thereof
US7517994B2 (en) 2003-11-19 2009-04-14 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
US7538120B2 (en) 2003-09-03 2009-05-26 Array Biopharma Inc. Method of treating inflammatory diseases
WO2010051933A2 (en) 2008-11-10 2010-05-14 Bayer Schering Pharma Aktiengesellschaft Substituted sulphonamido phenoxybenzamides
US7732616B2 (en) 2003-11-19 2010-06-08 Array Biopharma Inc. Dihydropyridine and dihydropyridazine derivatives as inhibitors of MEK and methods of use thereof
US7803839B2 (en) 2005-10-07 2010-09-28 Exelixis, Inc. Azetidines as MEK inhibitors for the treatment of proliferative diseases
EP2298768A1 (en) 2004-06-11 2011-03-23 Japan Tobacco, Inc. 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidine derivatives and related compounds for the treatment of cancer
WO2011047788A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted benzosulphonamides
WO2011047795A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted benzosulphonamides
WO2011047796A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted halophenoxybenzamide derivatives
US7999006B2 (en) 2006-12-14 2011-08-16 Exelixis, Inc. Methods of using MEK inhibitors
US8003651B2 (en) 2006-07-06 2011-08-23 Array Biopharma Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US8063050B2 (en) 2006-07-06 2011-11-22 Array Biopharma Inc. Hydroxylated and methoxylated pyrimidyl cyclopentanes as AKT protein kinase inhibitors
WO2012055953A1 (en) 2010-10-29 2012-05-03 Bayer Pharma Aktiengesellschaft Substituted phenoxypyridines
US8329701B2 (en) 2006-07-06 2012-12-11 Array Biopharma Inc. Dihydrofuro pyrimidines as AKT protein kinase inhibitors
US8377937B2 (en) 2007-07-05 2013-02-19 Array Biopharma Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US8618097B2 (en) 2007-07-05 2013-12-31 Array Biopharma, Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US8680114B2 (en) 2003-11-21 2014-03-25 Array Biopharma, Inc. AKT protein kinase inhibitors
US8835434B2 (en) 2008-01-09 2014-09-16 Array Biopharma, Inc. Hydroxylated pyrimidyl cyclopentanes as akt protein kinase inhibitors
US8846683B2 (en) 2007-07-05 2014-09-30 Array Biopharma, Inc. Pyrimidyl cyclopentanes as Akt protein kinase inhibitors
US8853216B2 (en) 2008-01-09 2014-10-07 Array Biopharma, Inc. Hydroxylated pyrimidyl cyclopentane as AKT protein kinase inhibitor
US9120789B2 (en) 2010-02-01 2015-09-01 Cancer Research Technology Limited 1-(5-tert-butyl-2-phenyl-2H-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)-phenyl]-urea and related compounds and their use in therapy
US9150549B2 (en) 2011-04-01 2015-10-06 Genentech, Inc. Combinations of AKT inhibitor compounds and erlotinib, and methods of use
US9155737B2 (en) 2007-12-19 2015-10-13 Institute Of Cancer Research: Royal Cancer Hospital (The) Pyrido[2,3-B]pyrazin-8-substituted compounds and their use
US9303040B2 (en) 2006-07-06 2016-04-05 Array Biopharma Inc. Substituted piperazines as AKT inhibitors
US9409886B2 (en) 2007-07-05 2016-08-09 Array Biopharma Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US9682082B2 (en) 2011-04-01 2017-06-20 Genentech, Inc. Combinations of AKT and MEK inhibitor compounds, and methods of use
US9708317B2 (en) 2013-11-25 2017-07-18 Cancer Research Technology Limited Process for the preparation of 8-(4-aminophenoxy)-4H-pyrido[2,3-B]pyrazin-3-one derivatives
US9725447B2 (en) 2013-11-25 2017-08-08 Cancer Research Technology Limited 1-(5-tert-butyl-2-aryl-pyrazol-3-yl)-3-[2-fluoro-4-[(3-oxo-4H-pyrido[2,3-b]pyrazin-8-yl)oxy]phenyl]urea derivatives as RAF inhibitors for the treatment of cancer
US11414396B2 (en) 2012-10-12 2022-08-16 Exelixis, Inc. Process for making compounds for use in the treatment of cancer

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DOP2003000556A (en) * 2002-01-23 2003-10-31 Warner Lambert Co ESTERES HYDROXAMATE ACID N- (4-PHENYL-REPLACED) -ANTRANILICO.
CA2559465A1 (en) * 2004-03-19 2005-10-06 Xiu-Min Li Herbal therapy for the treatment of asthma
EP1967516B1 (en) * 2005-05-18 2009-11-04 Array Biopharma, Inc. 4-(phenylamino)-6-oxo-1,6-dihydropyridazine-3-carboxamide derivatives as MEK inhibitors for the treatment of hyperproliferative diseases
KR101679082B1 (en) 2008-03-17 2016-11-23 더 스크립스 리서치 인스티튜트 Combined chemical and genetic approaches for generation of induced pluripotent stem cells
WO2012019113A2 (en) 2010-08-05 2012-02-09 Case Western Reserve University Inhibitors of erk for developmental disorders of neuronal connectivity
JP6182456B2 (en) 2010-12-22 2017-08-23 フェイト セラピューティクス，インコーポレイテッド Enhanced cell culture platform and iPSC reprogramming for single cell sorting
KR20240091064A (en) 2014-03-04 2024-06-21 페이트 세러퓨틱스, 인코포레이티드 Improved reprogramming methods and cell culture platforms
CN117737124A (en) 2015-10-16 2024-03-22 菲特治疗公司 Platform for inducing and maintaining ground state pluripotency

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5525625A (en) * 1995-01-24 1996-06-11 Warner-Lambert Company 2-(2-Amino-3-methoxyphenyl)-4-oxo-4H-[1]benzopyran for treating proliferative disorders
WO1998020868A1 (en) * 1996-11-15 1998-05-22 The Picower Institute For Medical Research Guanylhydrazones useful for treating diseases associated with t cell activation
WO1998037881A1 (en) * 1997-02-28 1998-09-03 Warner Lambert Company Method of treating or preventing septic shock by administering a mek inhibitor

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ513433A (en) * 1999-01-13 2003-05-30 Warner Lambert Co Benzoheterocycles, their use as MEK inhibitors and use in treating proliferative diseases such as cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5525625A (en) * 1995-01-24 1996-06-11 Warner-Lambert Company 2-(2-Amino-3-methoxyphenyl)-4-oxo-4H-[1]benzopyran for treating proliferative disorders
WO1998020868A1 (en) * 1996-11-15 1998-05-22 The Picower Institute For Medical Research Guanylhydrazones useful for treating diseases associated with t cell activation
WO1998037881A1 (en) * 1997-02-28 1998-09-03 Warner Lambert Company Method of treating or preventing septic shock by administering a mek inhibitor

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
TSANG F., ET AL.: "Effects of mitogen-activated protein kinase kinase inhibitor PD098059 on antigen challenge of guinea-pig airways in vitro" BRITISH JOURNAL OF PHARMACOLOGY, vol. 125, no. 1, September 1998 (1998-09), pages 61-68, XP000916809 *
WHELCHEL A., ET AL.: "Inhibition of ERK activation attenuates endothelin-stimulated airway smooth muscle cell proliferation" AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, vol. 16, no. 5, May 1997 (1997-05), pages 589-596, XP000916811 *

Cited By (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7345051B2 (en) 2000-01-31 2008-03-18 Genaera Corporation Mucin synthesis inhibitors
EP1255544A4 (en) * 2000-01-31 2005-02-02 Genaera Corp Mucin synthesis inhibitors
EP1255544A1 (en) * 2000-01-31 2002-11-13 Magainin Pharmaceuticals, Inc. Mucin synthesis inhibitors
US7504409B2 (en) 2000-01-31 2009-03-17 Genaera Corporation Mucin synthesis inhibitors
US6960614B2 (en) 2000-07-19 2005-11-01 Warner-Lambert Company Oxygenated esters of 4-lodo phenylamino benzhydroxamic acids
US7411001B2 (en) 2000-07-19 2008-08-12 Warner-Lambert Company Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids
US7132546B2 (en) 2000-12-22 2006-11-07 Ishihara Sangyo Kaisha, Ltd. Aniline derivatives or salts thereof and cytokine production inhibitors containing the same
EP1262176A1 (en) * 2001-05-09 2002-12-04 Warner-Lambert Company Method of treating or inhibiting neutrophil chemotaxis by administering a mek inhibitor
US6972298B2 (en) 2001-05-09 2005-12-06 Warner-Lambert Company Method of treating or inhibiting neutrophil chemotaxis by administering a MEK inhibitor
US7235537B2 (en) 2002-03-13 2007-06-26 Array Biopharma, Inc. N3 alkylated benzimidazole derivatives as MEK inhibitors
US7973170B2 (en) 2002-03-13 2011-07-05 Array Biopharma Inc. N3 alkylated benzimidazole derivatives as MEK inhibitors
US8193230B2 (en) 2002-03-13 2012-06-05 Array Biopharma Inc. Compositions comprising N3 alkylated benzimidazole derivatives as MEK inhibitors and methods of use thereof
US8193231B2 (en) 2002-03-13 2012-06-05 Array Biopharma Inc. Compositions comprising N3 alkylated benzimidazole derivatives as MEK inhibitors and methods of use thereof
US7425637B2 (en) 2002-03-13 2008-09-16 Array Biopharma Inc. N3 alkylated benzimidazole derivatives as MEK inhibitors
US8193229B2 (en) 2002-03-13 2012-06-05 Array Biopharma Inc. Method of treatment using N3 alkylated benzimidazole derivatives as MEK inhibitors
US8178693B2 (en) 2002-03-13 2012-05-15 Array Biopharma Inc. N3 alkylated benzimidazole derivatives as MEK inhibitors
US8513293B2 (en) 2002-03-13 2013-08-20 Array Biopharma Inc. Methods of treating a hyperproliferative disorder or inhibiting cell growth in a mammal
US8003805B2 (en) 2002-03-13 2011-08-23 Array Biopharma Inc. N3 alkylated benzimidazole derivatives as MEK inhibitors
US7230099B2 (en) 2003-09-03 2007-06-12 Array Biopharma, Inc. Heterocyclic inhibitors of MEK and methods of use thereof
US7538120B2 (en) 2003-09-03 2009-05-26 Array Biopharma Inc. Method of treating inflammatory diseases
US7060856B2 (en) 2003-10-21 2006-06-13 Warner-Lambert Company Polymorphic form of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide
US7576072B2 (en) 2003-11-19 2009-08-18 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
US8268852B2 (en) 2003-11-19 2012-09-18 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
US7772234B2 (en) 2003-11-19 2010-08-10 Array Biopharma Inc. Bicyclic inhibitors of MEK and methods of use thereof
US7732616B2 (en) 2003-11-19 2010-06-08 Array Biopharma Inc. Dihydropyridine and dihydropyridazine derivatives as inhibitors of MEK and methods of use thereof
US8431574B2 (en) 2003-11-19 2013-04-30 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
US8211920B2 (en) 2003-11-19 2012-07-03 Array Biopharma Inc. 6-oxo-1,6-dihydropyridine derivatives as inhibitors of MEK and methods of use thereof
US7485643B2 (en) 2003-11-19 2009-02-03 Array Biopharma Inc. Bicyclic inhibitors of MEK and methods of use thereof
US7517994B2 (en) 2003-11-19 2009-04-14 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
US8101611B2 (en) 2003-11-19 2012-01-24 Array Biopharma Inc. Substituted pyridazines inhibitors of MEK
US7598383B2 (en) 2003-11-19 2009-10-06 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
US8680114B2 (en) 2003-11-21 2014-03-25 Array Biopharma, Inc. AKT protein kinase inhibitors
WO2005054179A3 (en) * 2003-12-03 2005-08-04 Leo Pharma As Hydroxamic acid esters and pharmaceutical use thereof
US8034811B2 (en) 2003-12-03 2011-10-11 Leo Pharma A/S Hydroxamic acid esters and pharmaceutical use thereof
US7378423B2 (en) 2004-06-11 2008-05-27 Japan Tobacco Inc. Pyrimidine compound and medical use thereof
EP2298768A1 (en) 2004-06-11 2011-03-23 Japan Tobacco, Inc. 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidine derivatives and related compounds for the treatment of cancer
US8835443B2 (en) 2004-06-11 2014-09-16 Japan Tobacco Inc. Pyrimidine compound and medical use thereof
US11597699B2 (en) 2005-10-07 2023-03-07 Exelixis, Inc. MEK inhibitors and methods of their use
US7915250B2 (en) 2005-10-07 2011-03-29 Exelixis, Inc. Azetidines as MEK inhibitors for the treatment of proliferative diseases
US8362002B2 (en) 2005-10-07 2013-01-29 Exelixis, Inc. Azetidines as MEK inhibitors for the treatment of proliferative diseases
US7803839B2 (en) 2005-10-07 2010-09-28 Exelixis, Inc. Azetidines as MEK inhibitors for the treatment of proliferative diseases
WO2007049820A1 (en) 2005-10-28 2007-05-03 Takeda Pharmaceutical Company Limited Heterocyclic amide compound and use thereof
US9359340B2 (en) 2006-07-06 2016-06-07 Array Biopharma Inc. Hydroxylated and methoxylated pyrimidyl cyclopentanes as Akt protein kinase inhibitors
US8846681B2 (en) 2006-07-06 2014-09-30 Array Biopharma, Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US9303040B2 (en) 2006-07-06 2016-04-05 Array Biopharma Inc. Substituted piperazines as AKT inhibitors
US8329701B2 (en) 2006-07-06 2012-12-11 Array Biopharma Inc. Dihydrofuro pyrimidines as AKT protein kinase inhibitors
US8063050B2 (en) 2006-07-06 2011-11-22 Array Biopharma Inc. Hydroxylated and methoxylated pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US8003651B2 (en) 2006-07-06 2011-08-23 Array Biopharma Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US8853199B2 (en) 2006-07-06 2014-10-07 Array Biopharma, Inc. Hydroxylated and methoxylated pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US7999006B2 (en) 2006-12-14 2011-08-16 Exelixis, Inc. Methods of using MEK inhibitors
US8618097B2 (en) 2007-07-05 2013-12-31 Array Biopharma, Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US8377937B2 (en) 2007-07-05 2013-02-19 Array Biopharma Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US8846683B2 (en) 2007-07-05 2014-09-30 Array Biopharma, Inc. Pyrimidyl cyclopentanes as Akt protein kinase inhibitors
US9409886B2 (en) 2007-07-05 2016-08-09 Array Biopharma Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US9540372B2 (en) 2007-12-19 2017-01-10 Institute Of Cancer Research: Royal Cancer Hospital (The) Pyrido[2,3-b]pyrazin-8-substituted compounds and their use
US9155737B2 (en) 2007-12-19 2015-10-13 Institute Of Cancer Research: Royal Cancer Hospital (The) Pyrido[2,3-B]pyrazin-8-substituted compounds and their use
US8853216B2 (en) 2008-01-09 2014-10-07 Array Biopharma, Inc. Hydroxylated pyrimidyl cyclopentane as AKT protein kinase inhibitor
US8835434B2 (en) 2008-01-09 2014-09-16 Array Biopharma, Inc. Hydroxylated pyrimidyl cyclopentanes as akt protein kinase inhibitors
WO2010051933A2 (en) 2008-11-10 2010-05-14 Bayer Schering Pharma Aktiengesellschaft Substituted sulphonamido phenoxybenzamides
WO2011047795A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted benzosulphonamides
WO2011047788A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted benzosulphonamides
WO2011047796A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted halophenoxybenzamide derivatives
US9120789B2 (en) 2010-02-01 2015-09-01 Cancer Research Technology Limited 1-(5-tert-butyl-2-phenyl-2H-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)-phenyl]-urea and related compounds and their use in therapy
US9820976B2 (en) 2010-02-01 2017-11-21 Cancer Research Technology Limited 1-(5-tert-butyl-2-phenyl-2H-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)-phenyl]-urea and related compounds and their use in therapy
US9439893B2 (en) 2010-02-01 2016-09-13 Cancer Research Technology Limited 1-(5-tert-butyl-2-phenyl-2H-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-B]pyridin-7-yloxy)-phenyl]-urea and related compounds and their use in therapy
WO2012055953A1 (en) 2010-10-29 2012-05-03 Bayer Pharma Aktiengesellschaft Substituted phenoxypyridines
US9150549B2 (en) 2011-04-01 2015-10-06 Genentech, Inc. Combinations of AKT inhibitor compounds and erlotinib, and methods of use
US9610289B2 (en) 2011-04-01 2017-04-04 Genentech, Inc. Combinations of AKT inhibitor compounds and erlotinib, and methods of use
US9682082B2 (en) 2011-04-01 2017-06-20 Genentech, Inc. Combinations of AKT and MEK inhibitor compounds, and methods of use
US9717730B2 (en) 2011-04-01 2017-08-01 Genentech, Inc. Combinations of AKT inhibitor compounds and chemotherapeutic agents, and methods of use
US9346789B2 (en) 2011-04-01 2016-05-24 Genentech, Inc. Combinations of AKT inhibitor compounds and abiraterone, and methods of use
US10092567B2 (en) 2011-04-01 2018-10-09 Genentech, Inc. Combinations of AKT inhibitor compounds and chemotherapeutic agents, and methods of use
US9150548B2 (en) 2011-04-01 2015-10-06 Genentech, Inc. Combinations of AKT inhibitor compounds and vemurafenib, and methods of use
US11414396B2 (en) 2012-10-12 2022-08-16 Exelixis, Inc. Process for making compounds for use in the treatment of cancer
US9708317B2 (en) 2013-11-25 2017-07-18 Cancer Research Technology Limited Process for the preparation of 8-(4-aminophenoxy)-4H-pyrido[2,3-B]pyrazin-3-one derivatives
US9725447B2 (en) 2013-11-25 2017-08-08 Cancer Research Technology Limited 1-(5-tert-butyl-2-aryl-pyrazol-3-yl)-3-[2-fluoro-4-[(3-oxo-4H-pyrido[2,3-b]pyrazin-8-yl)oxy]phenyl]urea derivatives as RAF inhibitors for the treatment of cancer
US10100053B2 (en) 2013-11-25 2018-10-16 Cancer Research Technology Limited Process for the preparation of 8-(4-aminophenoxy)-4H-pyrido[2,3-b]pyrazin-3-one derivatives
US10167282B2 (en) 2013-11-25 2019-01-01 Cancer Research Technology Limited 1-(5-tert-butyl-2-aryl-pyrazol-3-yl)-3-[2-fluoro-4-[(3-oxo-4H-pyrido [2, 3-B]pyrazin- 8-yl)oxy]phenyl]urea derivatives as RAF inhibitors for the treatment of cancer

Also Published As

Publication number Publication date
EP1140062B1 (en) 2005-04-06
JP2002534380A (en) 2002-10-15
BR9916785A (en) 2001-10-23
AU2483000A (en) 2000-07-24
US6696440B1 (en) 2004-02-24
ATE292462T1 (en) 2005-04-15
EP1140062A2 (en) 2001-10-10
DE69924641D1 (en) 2005-05-12
WO2000040235A3 (en) 2000-11-09
US20040141924A1 (en) 2004-07-22
CA2350234A1 (en) 2000-07-13

Similar Documents

Publication Publication Date Title
EP1140062B1 (en) Treatment of asthma with mek inhibitors
AU776788C (en) Treatment of arthritis with MEK inhibitors
US6251943B1 (en) Method of treating or preventing septic shock by administering a MEK inhibitor
EP1140067A1 (en) Antiviral method using mek inhibitors
EP1140291B1 (en) Combination chemotherapy comprising a mitotic inhibitor and a mek inhibitor
AU756586C (en) 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives and their use as MEK inhibitors
US6310060B1 (en) 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives and their use as MEK inhibitors
WO2000035435A1 (en) Use of a mek inhibitor for preventing transplant rejection
US20040171632A1 (en) Combination chemotherapy
MXPA01005476A (en) Combination chemotherapy

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AL AU BA BB BG BR CA CN CR CU CZ DM EE GD GE HR HU ID IL IN IS JP KP KR LC LK LR LT LV MA MG MK MN MX NO NZ PL RO SG SI SK SL TR TT UA US UZ VN YU ZA

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AL AU BA BB BG BR CA CN CR CU CZ DM EE GD GE HR HU ID IL IN IS JP KP KR LC LK LR LT LV MA MG MK MN MX NO NZ PL RO SG SI SK SL TR TT UA US UZ VN YU ZA

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

WWE Wipo information: entry into national phase

Ref document number: PA/a/2001/004333

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 2350234

Country of ref document: CA

Ref country code: CA

Ref document number: 2350234

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 1999968153

Country of ref document: EP

ENP Entry into the national phase

Ref country code: JP

Ref document number: 2000 591992

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 09889091

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 1999968153

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 1999968153

Country of ref document: EP