EP1143957A2 - Traitement de l'arthrite a l'aide d'inhibiteurs de la mek - Google Patents

Traitement de l'arthrite a l'aide d'inhibiteurs de la mek

Info

Publication number
EP1143957A2
EP1143957A2 EP99966278A EP99966278A EP1143957A2 EP 1143957 A2 EP1143957 A2 EP 1143957A2 EP 99966278 A EP99966278 A EP 99966278A EP 99966278 A EP99966278 A EP 99966278A EP 1143957 A2 EP1143957 A2 EP 1143957A2
Authority
EP
European Patent Office
Prior art keywords
methyl
phenylamino
iodo
benzamide
bromo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99966278A
Other languages
German (de)
English (en)
Other versions
EP1143957A3 (fr
Inventor
David Thomas Dudley
Craig Mason Flory
Alan Robert Saltiel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Co LLC
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Filing date
Publication date
Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of EP1143957A2 publication Critical patent/EP1143957A2/fr
Publication of EP1143957A3 publication Critical patent/EP1143957A3/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to methods for preventing and treating rheumatoid arthritis or osteoarthritis by administering a compound characterized as an inhibitor of a kinase enzyme known as MEK (MAP kinase or ERK Kinase).
  • MEK MAP kinase or ERK Kinase
  • MEK phosphorylates and activates MAP kinase (also known as Erk).
  • the method is ideally practiced by administering a phenyl amine MEK inhibitor.
  • Arthritis is a debilitating disease that afflicts millions of people, and for which there currently are no cures. Several forms of arthritis are known.
  • Rheumatoid arthritis is characterized as a chronic systemic inflammatory disease, primarily of the joints, and generally marked by inflammatory changes in the synovial membranes and articular structures and by atrophy and rarefaction of the bones.
  • Osteoarthritis is a noninflammatory degenerative joint disease occurring most often in older persons. Characterized by degeneration of the articular cartilage, hypertrophy of bone at the margins, and changes in the synovial membrane, osteoarthritis is accompanied by pain and stiffness, particularly after prolonged physical activity. Osteoarthritis is also referred to as degenerative arthritis, hypertrophic arthritis, and degenerative joint disease.
  • the current treatments are designed to relieve the pain, and to diminish the symptoms. Most of the known treatments are anti-inflammatory agents such as NSAIDs and cyclooxygenase inhibitors.
  • This invention provides a method for preventing and treating arthritis, wherein the method comprises the step of administering to a mammal suspected of developing arthritis, or in need of treatment, an effective anti-arthritic amount of a MEK inhibitor, preferably a selective MEK inhibitor.
  • a MEK inhibitor preferably a selective MEK inhibitor.
  • Selective MEK inhibitors are those compounds which inhibit the MEK 1 and MEK 2 enzymes without substantial inhibition of other related enzymes.
  • One aspect of the invention provides a method for treating rheumatoid arthritis, said method comprising the step of administering a MEK inhibitor to a patient.
  • the invention provides a method for treating osteoarthritis, said method comprising administering a MEK inhibitor to a patient.
  • the invention provides a method for preventing and/or treating arthritis comprising the step of administering a therapeutically effective amount of a selective MEK inhibitor described in US 5,525,625, incorporated herein by reference in its entirety.
  • a selective MEK inhibitor is 2-(2-amino-
  • MEK inhibitors are compounds which inhibit one or more of the family of mammalian enzymes known as MAP kinase kinases, which phosphorylate the MAP kinase subfamily of enzymes (mitogen-associated protein kinase enzymes) referred to as MAP kinases or ERKs (extracellular signal-regulating enzymes such as ERK1 and ERK 2). These enzymes regulate phosphorylation of other enzymes and proteins within the mammalian body.
  • MEK 1 and MEK 2 are dual specificity kinases that are present in all cell types and play a critical role in the regulation of cell proliferation and differentiation in response to mitogens and a wide variety of growth factors and cytokines
  • the MEK inhibitor to be administered is a phenyl amine derivative of Formula I
  • R ⁇ is hydrogen, hydroxy, Cj-Cg alkyl, Ci -Cg alkoxy, halo, trifiuoromethyl, or CN.
  • R2 is hydrogen.
  • R3, R4, and R5 are independently selected from hydrogen, hydroxy, halo, trifiuoromethyl, Cj-Cg alkyl, Cj-Cg alkoxy, nitro, CN, and -(O or NH) m -(CH2) n -R9.
  • R9 is hydrogen, hydroxy,
  • R ⁇ Q 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-(Cj-Cg alkyl).
  • Z is COOR7, tetrazolyl, CONR 6 R 7 , CONHNRj 0 R ⁇ 1 , or CH 2 OR 7 .
  • R ⁇ and R7 independently are hydrogen, Cj-Cg alkyl, C2-Cg alkenyl,
  • C3-C10 (cycloalkyl optionally containing one, two, or three 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.
  • any of the foregoing alkyl, alkenyl, aryl, heteroaryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, C.;-C 6 alkoxy, amino, nitro, Ci- C 4 alkylamino, di(C ⁇ -C 4 )alkylamino, C 3 -C 6 cycloalkyl, phenyl,phenoxy, C 3 -C 5 heteroaryl, or C 3 -C 5 heteroaryloxy; or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
  • 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-t, 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
  • Examples of preferred embodiments include methods comprising a MEK inhibitor selected from Formula (I) Compound Table below.
  • the MEK inhibitor is a compound of Formula II
  • Ri a is hydrogen, hydroxy, Cj-Cg alkyl, Cj-Cg alkoxy, halo, trifiuoromethyl, or CN.
  • R2 a is hydrogen.
  • RjOa m d R-l la ⁇ s 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).
  • R 6a is hydrogen, Ci-Cg alkyl, (CO)-(C ⁇ -Cg alkyl), aryl, aralkyl, or C3-C10 cycloalkyl.
  • R ⁇ a is hydrogen, Cj-Cg alkyl,
  • any of the alkyl, alkenyl, aryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, C ⁇ -C 6 alkoxy, amino, nitro, C ⁇ -C 4 alkylamino, di(C ⁇ - C 4 )alkylamino, C 3 -C cycloalkyl, phenyl,phenoxy, C 3 -C 5 heteroaryl, or C 3 -C 5 heteroaryloxy; or R a and Rj 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 NR1 ⁇ a
  • Preferred embodiments of Formula (II) are those structures wherein: (a) R la is H, methyl, fluoro, or chloro; (b) R a is H; R 3a , R 4a , and R 5a are each H, Cl, nitro, or F; (c) R ⁇ s a is H; (d) R a is methyl, ethyl, 2-propenyl, propyl, butyl, pentyl, hexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylmethyl, or cyclopropylethyl; (e) the 4' position is I, rather than Br; (f) R 4a is F at the 4 position, para to the CO-
  • R 3a or R 5a is F;
  • at least one of R 3a , Ri a , and R 5a is F;
  • ⁇ a 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:
  • 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- methylpheny
  • the invention further provides methods of synthesis and synthetic intermediates.
  • This invention provides a method of preventing or treating arthritis in a patient which comprises the step of administering to a patient suffering from arthritis and in need of treatment, or to a patient at risk for developing arthritis, an effective anti-arthritic amount of a MEK inhibitor.
  • the invention provides a method of preventing and treating both rheumatoid arthritis and osteoarthritis.
  • the invention is preferably practiced by administering a phenyl amine MEK inhibitor of Formula (I) or Formula (II). Many of these MEK-inhibiting phenyl amine compounds are specific or selective MEK 1 and MEK 2 inhibitors.
  • Selective MEK 1 or MEK 2 inhibitors are those compounds which inhibit the MEK 1 or MEK 2 enzymes without substantially inhibiting other enzymes such as MKK3, ERK, 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 50 for one of the above-named other enzymes.
  • a selective inhibitor has an IC 50 that is at least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/5000 or less than that of its IC 50 for one or more of the above-named enzymes.
  • the mammals to be treated according to this invention are patients, not only humans but also animals such as horses and dogs, who have developed arthritis and are suffering from the pain and disfiguration associated with arthritis, or who are at risk for developing the disease, for example, those who have a family history of arthritis.
  • Those skilled in the medical art are readily able to identify individual patients who are afflicted with arthritis, as well as those who are susceptible to developing the disease.
  • the term "patient” means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, horses, and pigs.
  • the compounds of the present invention, which can be used to treat septic shock, are MEK inhibitors.
  • a MEK inhibitor is a compound that shows MEK inhibition when tested in the assays titled "Enzyme Assays" in United States Patent Number 5,525,625, column 6, beginning at line 35. The complete disclosure of United States Patent Number 5,525,625 is hereby inco ⁇ orated by reference.
  • An example of a MEK inhibitor is 2-(2-amino-3-methoxyphenyl)-
  • 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.
  • 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,
  • aryl and aryloxy substituted alkyl groups include phenylmethyl, 2-phenylethyl, 3-chlorophenylmethyl, l,l-dimethyl-3-(2-nitrophenoxy)butyl, and 3,4,5-trifluoronaphthylmethyl.
  • alkyl groups substituted by a heteroaryl or heteroaryloxy group include thienylmethyl, 2-furylethyl,
  • 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.
  • 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.
  • typical groups having both double and triple bonds include hex-2-en- 4-ynyl, 3-methyl-5-phenylpent-2-en-4-ynyl, and 3-thienyloxy-hex-3-en-5-ynyl.
  • cycloalkyl means a nonaromatic ring or fused rings. Examples include cyclopropyl, cyclobutyl, cyclopenyl, cyclooctyl, bicycloheptyl, adamantyl, and cyclohexyl.
  • the ring can optionally contain one, two, or three heteroatoms selected from O, S, or N.
  • Such groups include tetrahydrofliryl, 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.
  • 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
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well- known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan or mixtures of these substances, and the like.
  • inert diluents commonly used in the art, such as water or other solvents, solubil
  • 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.
  • 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 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.
  • 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, or prodrugs.
  • salts 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.
  • 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.)
  • esters of the compounds of this invention examples include Cj-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-Cg dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5 or 6 membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amines and C1-C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
  • 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 Drus 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.
  • organic or inorganic base such as pyridine, triethylamine, calcium carbonate, or sodium hydroxide.
  • the free acids can also be reacted with an alcohol of the formula HOR7
  • reaction of the benzoic acid with an alcohol can be carried out in the presence of a coupling agent.
  • Typical coupling reagents include
  • 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.
  • benzyl alcohols of the invention compounds of Formula (I) where Z is CH2OR6 and R6 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.
  • Aqueous HCl (10%) was added to the concentrate, and the solution was extracted with dichloromethane.
  • the organic phase was dried (MgSO_ ⁇ ) 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;
  • Example 2-30 By following the general procedure of Example 1 , the following benzoic acids and salts of Formula (I) were prepared.
  • 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 a Preparation of 5-chloro-2-fluoro-benzaldehyde To a solution of l-chloro-4-fluorobenzne (13.06 g, 0.1 mol) in THF
  • 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).
  • 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.
  • halo such as fluoro, chloro, bromo or iodo
  • 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.
  • 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,
  • 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 hexafluorophosphate
  • PyBOP benzotriazolyloxy
  • 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.
  • Yet another method for making invention compounds comprises reacting a phenylamino benzhydroxamic acid with an ester forming group as depicted in Scheme 5.
  • L is a leaving group such as halo
  • a base is triethylamine or diisopropylamine.
  • 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;
  • 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.
  • 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 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
  • 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.
  • Type Il-collagen-induced arthritis in mice is recognized as an experimental model of arthritis that has a number of pathologic, immunologic, and genetic features in common with rheumatoid arthritis in humans.
  • the disease is induced by immunization of DBA/1 inbred strain of mice with 100 micrograms of type II collagen (C II), which is the major component of joint cartilage.
  • C II type II collagen
  • the collagen was delivered to the mice by intradermal injection of a solution made up in Freund's complete adjuvant.
  • a progressive and inflammatory arthritis develops in the majority of the mice immunized, characterized by paw width increases of up to 100%).
  • a clinical scoring index is used to assess disease progression from erythema and edema (stage 1), joint distortion (stage 2), to joint ankylosis (stage 3).
  • the disease is variable in that it can affect one or all of the paws of the animal, resulting in total possible score of 12 for each mouse.
  • Histopathology of arthritic joints revealed synovitis, pannus formation, and cartilage and bone erosions. All mouse strains that are susceptible to CIA are high antibody responders to type II collagen, and there is a marked cellular response to C II.
  • the foregoing assay was carried out to evaluate the anti-arthritic activity of several doses of the compound 2-(2-chloro-4-iodophenylamino)-N- cyclopropylmethoxy-3,4-difluorobenzamide.
  • the compound also referred to as "PD 184352”
  • HPMC hydroxypropylmethyl cellulose
  • Tween 80 0.2% Tween 80.
  • HPMC hydroxypropylmethyl cellulose
  • the suspension was administered orally twice daily (once in the morning and once in the evening) in equally divided doses. All animals were fed laboratory chow, and given water ad libitum.
  • the assay was continued for 63 days, with disease scores being taken periodically throughout the study, and on Day 63, and averaged at the end of the study.
  • the results of the assay are presented in Pharmacological Table 1 below:
  • the phenyl amine compounds of Formulas I and II are potent anti-arthritic agents, and can be used to prevent and treat various forms of arthritis, including rheumatoid arthritis and osteoarthritis.
  • Several of the phenyl amine MEK inhibitors have been evaluated in an in vitro cell culture assay designed to measure the effect of MEK inhibitors on interleukin-1 (IL- 1 ) induced stromelysin production and phospo-ERK levels in rabbit synovial fibroblasts.
  • the stromelysin is a matrix metalloproteinase enzyme that is a causative factor in arthritis.
  • the phospho-ERK is an enzyme that is phosphorylated by a MEK enzyme, and is thus an indicator of MEK activity in cells.
  • New England White rabbits were euthanized with B-euthanasia administered IV with a 25 gauge needle in the marginal ear vein.
  • the synovium was immediately removed by the incision of the quadracep tendon and retracting the patella.
  • the synovium, with the infrapellar fat body, was then cut away from the patellar ligament and placed in sterile phosphate buffered saline (PBS) (Gibco BRL, Gaithersberg, MD).
  • PBS sterile phosphate buffered saline
  • the synovium was finely minced with a sterile scalpel and placed in a 50 mL tube containing 6 mL of a solution of 4 mg collagenase type I (Gibco BRL, Gaithersberg, MD)/mL PBS.
  • the mixture was incubated for 3 hours at 37°C. During the incubation, the 50 mL tube was gently swirled 4 to 6 times. The synoviocytes were then washed twice in media (the media composition is described below). Washed cells were seeded into one T-75 plastic cell culture flask and incubated at 37°C in 5% CO2. After reaching
  • the media used in the foregoing assay was prepared as follows, utilizing commercial reagents acquired from Gibco BRL (Gaithersberg, MD) unless otherwise stated. To each 500 mL bottle of alpha-modified Eagles medium
  • Pharmacological Table 3 presents the nanomolar dose of test compound required to cause a 50% inhibition of stromelysin expression (IC50).
  • PD 203311 20 In addition, a Western blot analysis of phospho-ERK levels in cell cultures was performed. Pharmacological Table 4 presents the % inhibition of ERK 1/2 phosphorylation caused by a phenyl amine MEK inhibitor.
  • Cells were lysed with ImL lysis buffer (containing NaCl (70 mM), B-glycerol phosphate (50 mM), 1M HEPES (10 mM), Triton X-100 (1%)) per T25. The mixture was transferred to microcentrifuge tubes, and spun at 2500 x g for 15 minutes. After removing the supernatant, the protein assay was performed. The samples were run on a 10% Tris-Glycine gel, and transferred to nitrocellulose.
  • the blots were then probed with a phospho-p44/42 MAP kinase antibody followed by the secondary Ab (goat anti rabbit HRP conjugated), coated with the ECL detection reagent, and exposed to film.
  • the amount of phospo-ERK present was determined by relative densitometry.
  • the method of this invention has also been established in in vivo assays utilizing New Zealand White rabbits in which cartilage degradation was induced by interleukin 1 -alpha injections into the knee joints.
  • Adult male rabbits weighing about 3 kg were anesthetized with 5 mg/kg of rompun and 10-15 mg/kg of ketamine.
  • Test compounds were suspended in a vehicle of 0.5% aqueous hydroxypropyl methyl cellulose and 0.2% Tween 80. The suspensions were administered by oral gavage to the animals.
  • human recombinant IL-l ⁇ Genzyme, Cambridge, MA
  • the contralateral joint received an equal volume of vehicle (phosphate buffered saline/0.2% fetal bovine serum).
  • vehicle phosphate buffered saline/0.2% fetal bovine serum.
  • the animals were euthanized after 24 hours after the IL-1 injection, and the extent of cartilage degradation was determined by measuring the proteoglycan content of the articular cartilage from the femoral condyles with a dimethylene blue dye assay kit. Analysis was done spectrophotometrically, and the percent of inhibition of proteoglycan loss in the treated joint compared to the non-treated joint was determined.
  • the results of this in vivo assay for several of the selective MEK inhibitors of Formulas I and II are presented below in Pharmacological Table 5.
  • rat adjuvant-induced polyarthritis (rat AIP) was induced following published procedures.
  • Outbred male Wistar rats (100-115 gms) were obtained from Charles River Labs 2 - 5 days prior to initiation of the study. Rats were injected subcutaneously in the distal third of the tail with 1 mg Mycobacterium butyricum suspended in paraffin oil using glass tuberculin syringes and 25 gauge needles on day 0. The Mycobacterium butyricum suspension was achieved by sonicating in paraffin oil for 10 minutes with the vessel immersed in an ice bath. After all the rats in the study were immunized, they were randomized into groups. In the therapeutic study, randomization was done on day 14.
  • IL-1 arthritis (IL-1) model
  • adult male New Zealand White rabbits were anesthetized with rompun (10 mg/kg) and ketamine (50 mg/kg) (im).
  • Twenty-five nanograms IL-1 was injected into one knee joint space through the suprapatella ligament (using sterile techniques).
  • the contralateral joint received an equal volume of vehicle.
  • the knees were first shaved and then swabbed with a surgical disinfectant prior to intraarticular injection.
  • the animals were euthanized after 24 hours, the articular cartilage scraped from the femoral condyles and tibial plateaus and weighed, and the extent of cartilage degradation determined by a standard dimethylene blue assay.
  • Test compound was administered by oral gavage one hour prior to IL-1 administration.

Abstract

L'invention se rapporte à un procédé de prévention et de traitement de l'arthrite chez un mammifère souffrant d'arthrite et nécessitant un traitement, ou supposé enclin à souffrir d'arthrite. Ledit procédé consiste à administrer une quantité anti-arthritique efficace d'un inhibiteur de la kinase MEK, et notamment un composé représenté par la formule (I) et la formule (II).
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NZ515567A (en) * 1999-07-16 2004-03-26 Warner Lambert Co Method for treating chronic pain using MEK inhibitors
US7030119B1 (en) 1999-07-16 2006-04-18 Warner-Lambert Company Method for treating chronic pain using MEK inhibitors
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KR100609800B1 (ko) 2006-08-09
HUP0104693A2 (hu) 2002-03-28
JP2002532415A (ja) 2002-10-02
HUP0104693A3 (en) 2003-12-29
KR20010093840A (ko) 2001-10-29
AU776788B2 (en) 2004-09-23
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WO2000035436A2 (fr) 2000-06-22
CA2346448A1 (fr) 2000-06-22

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