EP1202726A2 - Method for treating chronic pain using mek inhibitors - Google Patents

Method for treating chronic pain using mek inhibitors

Info

Publication number
EP1202726A2
EP1202726A2 EP00943383A EP00943383A EP1202726A2 EP 1202726 A2 EP1202726 A2 EP 1202726A2 EP 00943383 A EP00943383 A EP 00943383A EP 00943383 A EP00943383 A EP 00943383A EP 1202726 A2 EP1202726 A2 EP 1202726A2
Authority
EP
European Patent Office
Prior art keywords
phenylamino
iodo
methyl
benzamide
difluoro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00943383A
Other languages
German (de)
French (fr)
Inventor
Alistair Dixon
Kevin Lee
Robert Denham Pinnock
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Co LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of EP1202726A2 publication Critical patent/EP1202726A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—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
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4

Definitions

  • the invention features a method for treating chronic pain, using MEK inhibitors.
  • Chronic pain includes neuropathic pain, and chronic inflammatory pain.
  • neuropathic pain may be, for example, a deep ache, a burning sensation, or hypersensitivity to touch.
  • Diseases or conditions associated with neuropathic pain include, without limitation, diabetic neuropathy, causalgia, plexus avulsion, neuroma, vasculitis, crush injury, viral infections (e.g., herpes virus infection or HIV), constriction injury, tissue injury, nerve injury from the periphery to the central nervous system, limb amputation, hypothyroidism, uremia, chronic alcoholism, post-operative pain, arthritis, back pain, and vitamin deficiencies .
  • Infections such as herpes zoster (shingles) can cause nerve inflammation and produce postherpetic neuralgia, a chronic burning localized to the area of viral infection.
  • Hyperalgesia is when an already noxious stimulus becomes more painful, and allodynia, when a previously non-noxious stimulus becomes painful (such as contact of clothing or a breeze).
  • Reflex sympathetic dystrophy is accompanied by swelling and sweating or changes in local blood flow, tissue atrophy, or osteoporosis.
  • Causalgia including severe burning pain and swelling, sweating, and changes in blood flow, may follow an injury or disease of a major nerve such as the sciatic nerve.
  • neuropathic pain may also be induced by cancer or chemotherapy.
  • Neuropathic pain is currently treated with anticonvulsants such as carbamazepine and antidepressants such as amitryptaline.
  • NSAIDS and opioids generally have little effect (Fields et al 1994 Textbook of Pain p 991- 996 (pub: Churchill Livingstone), James & Page 1994 J.Am. Pediatr. Med.Assoc, 8: 439-447, Galer, 1995 Neurology 45 S17-S25.
  • Neuropathic conditions that have been treated with gabapentin include: postherpetic neuralgia, postpoliomyelitis, CPRM, HIV-related neuropathy, trigeminal neuralgia, and reflex sympathetic dystrophy (RSD).
  • the generally weak efficacy of antiinflammatory agents suggests that the mechanism for chronic pain is separate from hyperalgesia.
  • the invention features a method for treating chronic pain, which method includes the step of administering a composition including a MEK inhibitor to a patient in need of such treatment.
  • Chronic pain includes neuropathic pain, idiopathic pain, and pain associated with vitamin deficiencies, uremia, hypothyroidism post-operative pain, arthritis, back pain, and chronic alcoholism.
  • the invention also features compounds as disclosed, formulated for the treatment of chronic pain.
  • Such a composition may include one or more MEK inhibitor compounds having a structure disclosed in patent applications PCT/US98/13106, international filing date June 24, 1998, and PCT/US98/13105, international filing date June 24, 1998.
  • MEK inhibitors include 4-bromo and 4-iodo phenylamino benzhydroxamic acid derivatives which are kinase inhibitors and as such are useful for treating proliferative diseases such as cancer, psoriasis, and restenosis.
  • the compounds are defined by Formula I
  • Rl is hydrogen, hydroxy, Ci-C ⁇ alkyl, C-i-Cs alkoxy, halo, trifluoromethyl, or CN;
  • R2 is hydrogen;
  • R3, R4, and R5 independently are hydrogen, hydroxy, halo, trifluoromethyl,
  • R6 is hydrogen, C-
  • R7 is hydrogen, C ⁇ -Cg alkyl, C2-C8 alkenyl, C2-C8 alkynyl,
  • C3-C10 (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NRg); or RQ and R7 taken together with the N-O 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 NRI QRH ; and wherein any of the foregoing alkyl, alkenyl, and alkynyl groups can be unsubstituted or substituted by cycloalkyl (or cycloalkyl optionally containing a heteroatom selected from O, S, or NRg), aryl, aryloxy, heteroaryl, or heteroaryloxy.
  • Preferred compounds have Formula
  • , R3, R4, R5, RQ, and R7 are as defined above.
  • is methyl or halo
  • R3, R4, and R5 are halo such as fluoro or bromo.
  • R wherein R ⁇
  • is methyl or halo such as F, Br, Cl, and I
  • R3 is hydrogen or halo such as fluoro
  • R4 is halo such as fluoro
  • R5 is hydrogen or halo such as fluoro or bromo.
  • MEK inhibitors include 4-bromo and 4-iodo phenylamino benzoic acid derivatives which are selective MEK kinase inhibitors.
  • the compounds are defined by Formula 1(A)
  • R-l is hydrogen, hydroxy, C-i-C ⁇ alkyl, Ci-Cs alkoxy, halo, trifluoromethyl, or CN;
  • R2 is hydrogen;
  • R3 > R4, and R5 independently are hydrogen, hydroxy, halo, trifluoromethyl, C-i-C ⁇ alkyl, C ⁇
  • 1 independently are hydrogen or C ⁇
  • Z is COOR7, tetrazolyl, CONR6R7, CONHNR1 nRl 1 or CH2OR7;
  • RQ and R7 independently are hydrogen, C ⁇
  • C2-C8 alkynyl C - Ci-Cs 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 RQ 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, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, and the pharmaceutically acceptable salts thereof.
  • Preferred compounds have Formula ll(A)
  • , R3, R4, R5, RQ, and R7 are as defined above.
  • is methyl or halo
  • R3, R4, and R5 are halo such as fluoro or bromo.
  • the compounds of Formula 11(A) are carboxylic acids when R7 is hydrogen, and are esters when R7 is other than hydrogen.
  • Compounds which are analogous to the acids in physical and biological properties are tetrazolyl derivatives of Formula Ma
  • Another preferred group of compounds are amides Formula 111(A)
  • the benzyl alcohols of the invention have Formula IV(A)
  • the most preferred compounds are those wherein R-l is methyl, R3 is hydrogen or halo such as fluoro, R4 is halo such as fluoro, and R5 is hydrogen or halo such as fluoro, bromo, or chloro.
  • Representative compounds have the formulas
  • Br or Preferred embodiments for this invention include methods using one or more of the following compounds: (a) said MEK inhibitor has a structure selected from: 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide; N-Cyclopropylmethoxy-3,4,5-trifuoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Cyclopropylmethoxy-3,4,5-trifuoro-2-(4-iodo-2-methyl-phenylamino)- benzamide, potassium salt;
  • said MEK inhibitor has a structure selected from:
  • said MEK inhibitor has a structure selected from:
  • said MEK inhibitor has a structure selected from:
  • This invention also provides pharmaceutical formulations adapted for the treatment of chronic pain, said formalities comprising a disclosed compound together with a pharmaceutically acceptable excipient, diluent, or carrier.
  • Preferred formulations include any of the foregoing preferred compounds together with an excipient, diluent, or carrier.
  • the disclosed compounds are potent and selective inhibitors of kinase enzymes, particularly MEK-
  • FIG. 1 is a bar graph representing the paw withdrawal threshold (PWT) in grams as a function of time in days.
  • the empty, cross-hatched, and single- hatched bars are vehicle, PD 198306, and pregabalin, respectively.
  • the arrows indicate time of drug administration (30 mg/kg, p.o.).
  • FIG 2. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days.
  • FIG. 3. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days.
  • Baseline (BL) measurements were taken before treatment. Animals received a single p.o. administration of PD 198306 (3-30mg/kg), or pregabalin
  • FIG. 4. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days.
  • BL Baseline
  • FIG. 6 is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days .
  • FIG. 7. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days.
  • FIG. 8 is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments.
  • MEK enzymes are dual specificity kinases involved in, for example, immunomodulation, inflammation, and proliferative diseases such as cancer and restenosis, as well as pair.
  • Proliferative diseases are caused by a defect in the intracellular signaling system, or the signal transduction mechanism of certain proteins.
  • Defects include a change either in the intrinsic activity or in the cellular concentration of one or more signaling proteins in the signaling cascade .
  • the cell may produce a growth factor that binds to its own receptors, resulting in an autocrine loop, which continually stimulates proliferation. Mutations or overexpression of intracellular signaling proteins can lead to spurious mitogenic signals within the cell. Some of the most common mutations occur in genes encoding the protein known as Ras, a G-protein that is activated when bound to GTP, and inactivated when bound to GDP.
  • Ras leads in turn to the activation of a cascade of serine/threonine kinases.
  • One of the groups of kinases known to require an active Ras-GTP for its own activation is the Raf family. These in turn activate MEK (e.g., MEKi and MEK2) which then activates MAP kinase, ERK (ERK T and ERK 2 ).
  • MEK e.g., MEKi and MEK2
  • ERK ERK T and ERK 2
  • Blockade of downstream Ras signaling for example by use of a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants.
  • Ras is not itself a protein kinase, it participates in the activation of Raf and other kinases, most likely through a phosphorylation mechanism.
  • Raf and other kinases phosphorylate MEK on two closely adjacent serine residues, s218 anc
  • MEK in turn phosphorylates MAP kinase on both a tyrosine, ⁇ 185 anc
  • MAP kinase This double phosphorylation activates MAP kinase at least 100-fold. Activated MAP kinase can then catalyze the phosphorylation of a large number of proteins, including several transcription factors and other kinases. Many of these MAP kinase phosphorylations are mitogenically activating for the target protein, such as a kinase, a transcription factor, or another cellular protein. In addition to Raf-1 and MEKK, other kinases activate MEK, and MEK itself appears to be a signal integrating kinase. Current understanding is that MEK is highly specific for the phosphorylation of MAP kinase.
  • MEK does not phosphorylate peptides based on the MAP kinase phosphorylation sequence, or even phosphorylate denatured MAP kinase.
  • MEK also appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK may require a prior strong interaction between the two proteins.
  • MEK inhibitor PD 198306 has been investigated in two animal models of neuropathic pain by assessing static allodynia with von Frey hairs.
  • PD 198306 had no effect in the model of chronic constriction injury of the sciatic nerve (CCI). However, after repeated administration (3 doses over two days) it had a transient effect in the diabetic neuropathy model (streptozocin). This may be due to disorders of the blood- brain barrier induced by the diabetic condition in these animals, thus allowing central action of the compound.
  • Alkyl groups include aliphatic (i.e., hydrocarbyl or hydrocarbon radical structures containing hydrogen and carbon atoms) with a free valence. Alkyl groups are understood to include straight chain and branched structures. Examples include methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, t- butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl, 2,3-dimethylhexyl, 1 ,1- dimethylpentyl, heptyl, and octyl. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Alkyl groups can be substituted with 1 , 2, 3 or more substituents which are independently selected from halo (fluoro, chloro, bromo, or iodo), hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical)oxy.
  • substituents are independently selected from halo (fluoro, chloro, bromo, or iodo), hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical)oxy.
  • alkenyl groups are analogous to alkyl groups, but have at least one double bond (two adjacent sp 2 carbon atoms).
  • alkynyl groups have at least one triple bond (two adjacent sp carbon atoms).
  • Unsaturated alkenyl or alkynyl groups may have one or more double or triple bonds, respectively, or a mixture thereof; like alkyl groups, unsaturated groups may be straight chain or branched, and they may be substituted as described both above for alkyl groups and throughout the disclosure by example.
  • alkenyls, alkynyls, and substituted forms include cis-2-butenyl, trans-2-butenyl, 3-butynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 3-methyl(5-phenyl)-4-pentynyl, 2-hydroxy-2-propynyl, 2-methyl-2-propynyl, 2- propenyl, 4-hydroxy-3-butynyl, 3-(3-fluorophenyl)-2-propynyl, and 2-methyl-2- propenyl.
  • alkenyls and alkynyls can be C 2- or C 2 _ 8 , for example, and are preferably C 3 . 4 or C 3 . 8 - More general forms of substituted hydrocarbon radicals include hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, and corresponding forms for the prefixes amino-, halo- (e.g., fluoro-, chloro-, or bromo-), nitro-, alkyl-, phenyl-, cycloalkyl- and so on, or combinations of substituents.
  • halo- e.g., fluoro-, chloro-, or bromo-
  • substituted alkyls include hydroxyalkyl, aminoalkyl, nitroalkyl, haloalkyl, alkylalkyl (branched alkyls, such as methylpentyl), (cycloalkyl)alkyl, phenylalkyl, alkoxy, alkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, (heterocyclic radical)alkyl, and (heterocyclic radical)oxyalkyl.
  • Ri thus includes hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocycloalkyl, aminoaryl, alkylalkenyl, (alkylaryl)alkyl, (haloaryl)alkyl, (hydroxyaryl)alkynyl, and so forth.
  • R A includes hydroxyalkyl and aminoaryl
  • R B includes hydroxyalkyl, aminoalkyl, and hydroxyalkyl(heterocyclic radical)alkyl.
  • Heterocyclic radicals which include but are not limited to heteroaryls, include: furyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, pyrrolyl, imidazolyl, 1 ,3,4-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, and their nonaromatic counterparts.
  • heterocyclic radicals include piperidyl, quinolyl, isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyrrolyl, pyrrolidinyl, octahydroindolyl, octahydrobenzothiofuranyl, and octahydrobenzofuranyl.
  • 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 5 o for one of the above-named other enzymes.
  • a selective inhibitor has an IC 5 o that is at least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/5000, or less than that of its ICso or one or more of the above-named enzymes.
  • 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, or amino.
  • Typical substituted aryl groups include 3-fluorophenyl, 3,5-dimethoxyphenyl, 4-nitronaphthyl, 2-methyl- 4-chloro-7-aminofluorenyl, and the like.
  • aryloxy means an aryl group bonded through an oxygen atom, for example phenoxy, 3-bromophenoxy, naphthyloxy, and 4-methyl- 1 -fluorenyloxy.
  • Heteroaryl means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from four to eleven carbon atoms and one, two, or three heteroatoms selected from O, S, or N. Examples include furyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, thiazolyl, xanthenyl, pyronyl, indolyl, pyrimidyl, naphthyridyl, pyridyl, 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, or amino.
  • 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.
  • C-i-Cs alkyl means straight and branched chain aliphatic groups having from one to eight carbon atoms.
  • -C8 alkyl groups include methyl, ethyl, isopropyl, tert.-butyl, 2,3-dimethylhexyl, and 1 ,1-dimethylpentyl.
  • the alkyl groups can be unsubstituted or substituted by cycloalkyl, cycloalkyl containing a heteroatom selected from O, S, or NRg, aryl, aryloxy, heteroaryl, or heteroaryloxy, as those terms are defined above.
  • Examples of aryl and aryloxy substituted alkyl groups include phenylmethyl, 2-phenylethyl, 3-chlorophenylmethyl, 1 ,1-dimethyl-3-(2-nitrophenoxy)butyl, and 3,4,5-trifluoronaphthylmethyl.
  • Examples of alkyl groups substituted by a heteroaryl or heteroaryloxy group include thienylmethyl, 2-furylethyl, 6-furyloxyoctyl, 4-methylquinolyloxymethyl, and 6-isothiazolylhexyl.
  • Cycloalkyl substituted alkyl groups include cyclopropylmethyl, 2-cyclopentylethyl, 2-piperidin-1 -ylethyl, 3-(tetrahydropyran-2-yl)propyl, and cyclobutylmethyl.
  • C2"C ⁇ Alkenyl means a straight or branched carbon chain having one or more double bonds. Examples include but-2-enyl, 2-methyl-prop-2-enyl, 1 ,1-dimethyl-hex-4-enyl, 3-ethyl-4-methyl-pent-2-enyl, and 3-isopropyl-pent- 4-enyl.
  • alkenyl groups can be substituted with aryl, aryloxy, heteroaryl, or heteroyloxy, for example 3-phenylprop-2-enyl, 6-thienyl-hex-2-enyl, 2-furyloxy- but-2-enyl, and 4-naphthyloxy-hex-2-enyl.
  • C2-C8 Alkynyl means a straight or branched carbon chain having from two to eight carbon atoms and 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 by aryl, aryloxy, heteroaryl, or heteroaryloxy, for example 4-(2-fluorophenyl)-but-3-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.
  • C3-C-10 cycloalkyl means a non-aromatic ring or fused rings containing from three to ten carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopenyl, cyclooctyl, bicycloheptyl, adamantyl, and cyclohexyl.
  • the ring can optionally contain a heteroatom selected from O, S, or NRg.
  • R3, R4, and R5 can include groups defined by the term (O or NH) m -
  • aryl means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from five to twelve carbon atoms.
  • aryl groups examples include phenyl, naphthyl, and fluorenyl.
  • the aryl may be substituted by one, two, or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino, or dialkylamino.
  • Typical substituted aryl groups include 3-fluorophenyl, 3,5-dimethoxyphenyl, 4-nitronaphthyl, 2-methyl-4-chloro-7-aminofluorenyl, and the like.
  • aryloxy means an aryl group bonded through an oxygen atom, for example phenoxy, 3-bromophenoxy, naphthyloxy, and 4-methyl- 1-fluorenyloxy.
  • Heteroaryl means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from four to eleven carbon atoms and one, two, or three heteroatoms selected from O, S, or N. Examples include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, xanthenyl, pyronyl, indolyl, pyrimidyl, naphthyridyl, pyridyl, benzinnidazolyl, and triazinyl.
  • heteroaryl groups can be unsubstituted or substituted by one, two, or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino, or dialkylamino.
  • substituted heteroaryl groups include chloropyranyl, methy ⁇ thienyl, 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.
  • -C8 alkyl means straight and branched chain aliphatic groups having from one to eight carbon atoms, preferably one to four.
  • -C8 alkyl groups include methyl, ethyl, isopropyl, tert.-butyl,
  • alkyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, as those terms are defined herein.
  • Typical substituted alkyl groups include chloromethyl, 3-hydroxypropyl, 2-dimethylaminobutyl, and 2-(hydroxymethylamino)ethyl.
  • Examples of aryl and aryloxy substituted alkyl groups include phenylmethyl, 2-phenylethyl, 3-chlorophenylmethyl, 1 ,1-dimethyl-3-(2-nitrophenoxy)butyl, and 3,4,5-trifluoronaphthylmethyl.
  • Examples of alkyl groups substituted by a heteroaryl or heteroaryloxy group include thienylmethyl, 2-furylethyl, 6-furyloxyoctyl, 4-methylquinolyloxymethyl, and 6-isothiazolylhexyl.
  • Cycloalkyl substituted alkyl groups include cyclopropylmethyl, 2-cyclohexyethyl, piperidyl-2-methyl, 2-(piperidin-1-yl)- ethyl, 3-(morpholin-4-yl)propyl.
  • C2-C8 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.
  • C2-C8 Alkynyl means a straight or branched carbon chain having from two to eight carbon atoms and 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.
  • C3-C-10 cycloalkyl means a nonaromatic ring or fused rings containing from three to ten carbon atoms.
  • 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 NRg.
  • Such groups include tetrahydrofuryl, tetrahydropyrrolyl, octahydrobenzofuranyl, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, octahydroindolyl, and octahydrobenzothiofuranyl.
  • the cycloalkyl groups can be substituted with the same substituents as an alkyl and alkenyl groups, for example, halo, hydroxy, aryl, and heteroaryloxy. Examples include 3-hydroxycyclohexyl, 2-aminocyclopropyl, 2-phenylpyrrolidinyl, and 3-thienylmorpholine-1-yl.
  • Rg and R7 can be taken together with the nitrogen to which they are attached to complete a cyclic ring having from 3 to 10 members, which may contain 1 , 2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl.
  • cyclic rings examples include piperazinyl, piperidyl, pyrrolidinyl, morpholino, N-methylpiperazinyl, aziridynyl, and the like.
  • Such rings can be substituted with halo, hydroxy, alkyl, alkoxy, amino, alkyl, and dialkylamino, aryl, aryloxy, heteroaryl, and heteroaryloxy.
  • Typical examples include 3-hydroxy-pyrrolidinyl, 2-fluoro-pipehndyl, 4-(2-hydroxyethyl)-piperidinyl, and 3-thienylmorpholino.
  • the 4-bromo and 4-iodo phenylamino benzhydroxamic 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 phenylamino benzoic acid, and then reacting the benzoic acid phenylamino derivative with a hydroxylamine derivative. This process is depicted in Scheme 1.
  • 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 the aniline derivative 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 HNR ⁇ OR7 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-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
  • 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 2.
  • Yet another method for making invention compounds comprises reacting a phenylamino benzhydroxamic acid with an ester forming group as depicted in Scheme 3.
  • L is a leaving group such as halo
  • a base is triethylamine or diisopropylamine.
  • the 2-(4-bromo and 4-iodo phenylamino)-benzoic acid derivatives of Formula 1(A) can be prepared from commercially available starting materials utilizing synthetic methodologies well-known to those skilled in organic chemistry and illustrated in synthetic examples 1A - 224A below.
  • 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 (A).
  • 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 (eg, Formula IA, 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.
  • benzyl alcohols of the invention compounds of Formula l(A) where Z is CH2 ⁇ R ⁇ and RQ is hydrogen, are readily prepared by reduction of the corresponding benzoic acid according to the following scheme
  • 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.
  • compositions are useful as both prophylactic and therapeutic treatments for diseases or conditions relating to chronic pain, including neuropathic pain, as provided in the Summary section, as well as diseases or conditions modulated by the MEK cascade.
  • the disclosed method relates to postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, crush injury, constriction injury, tissue injury, post-surgical pain, arthritis pain, or limb amputation
  • local injuries can be treated with local or topical administration.
  • Chronic pain affecting the entire body such as diabetic neuropathy can be treated with systemic administration (injection or orally) of a disclosed composition.
  • Treatment for chronic pain (e.g., post-operative pain) confined to the lower body can be administered centrally, e.g., epidurally.
  • Formulations and methods of administration can include the use of more than one MEK inhibitor, or a combination of a MEK inhibitor and another pharmaceutical agent, such as an anti-inflammatory, analgesic, muscle relaxing, or anti-infective agent.
  • Preferred routes of administration are oral, intrathecal or epidural, subcutaneous, intravenous, intramuscular, and, for non-human mammals, intraplantar, and are preferably epidural.
  • an effective amount will be between 0.1 and 1000 mg/kg per day, preferably between 1 and 300 mg/kg body weight, and daily dosages will be between 10 and 5000 mg for an adult subject of normal weight.
  • Commercially available capsules or other formulations such as liquids and film-coated tablets) of 100 mg, 200 mg, 300 mg, or 400 mg can be administered according to the disclosed methods.
  • Dosage unit forms include tablets, capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted for subdivision into individual doses.
  • Dosage unit forms can also be adapted for various methods of administration, including controlled release formulations, such as subcutaneous implants.
  • Administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intrape toneal, intravesical, local (drops, powders, ointments, gels, or cream), and by inhalation (a buccal or nasal spray).
  • Parenteral formulations include pharmaceutically acceptable aqueous or nonaqueous solutions, dispersion, suspensions, emulsions, and sterile powders for the preparation thereof.
  • carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils, and injectable organic esters such as ethyl oleate. Fluidity can be maintained by the use of a coating such as lecithin, a surfactant, or maintaining appropriate particle size.
  • Carriers for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrating agents, (e) solution retarders, (f) absorption acccelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and 0) propellants.
  • Compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents; antimicrobial agents such as parabens, chlorobutanol, phenol, and sorbic acid; isotonic agents such as a sugar or sodium chloride; absorption-prolonging agents such as aluminum monostearate and gelatin; and absorption-enhancing agents.
  • adjuvants such as preserving, wetting, emulsifying, and dispensing agents
  • antimicrobial agents such as parabens, chlorobutanol, phenol, and sorbic acid
  • isotonic agents such as a sugar or sodium chloride
  • absorption-prolonging agents such as aluminum monostearate and gelatin
  • absorption-enhancing agents such as aluminum monostearate and gelatin.
  • the invention provides the disclosed compounds and closely related, pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, hydrates or solvated forms thereof; masked or protected forms; and racemic mixtures, or enantiomerically or optically pure forms.
  • Pharmaceutically acceptable salts, esters, and amides include carboxylate salts (e.g., C ⁇ -8 alkyl, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclic), amino acid addition salts, esters, and amides which are within a reasonable benefit/risk ratio, pharmacologically effective, and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.
  • Representative salts include 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 laurylsulfonate.
  • alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine.
  • alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium
  • non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine.
  • amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine.
  • Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C ⁇ -6 alkyl amines and secondary di (C ⁇ _ 6 alkyl) amines.
  • Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms.
  • Preferred amides are derived from ammonia, C 1 . 3 alkyl primary amines, and di (C ⁇ -2 alkyl)amines.
  • Representative pharmaceutically acceptable esters of the invention include C ⁇ -7 alkyl, C 5 -7 cycloalkyl, phenyl, and phenyl(C .- ⁇ jalkyl esters.
  • Preferred esters include methyl esters.
  • the invention also includes disclosed compounds having one or more functional groups (e.g., hydroxyl, amino, or carboxyl) masked by a protecting group. Some of these masked or protected compounds are pharmaceutically acceptable; others will be useful as intermediates. Synthetic intermediates and processes disclosed herein, and minor modifications thereof, are also within the scope of the invention.
  • Hydroxyl protecting groups include: ethers, esters, and protection for 1 ,2- and 1 ,3-diols.
  • the ether protecting groups include: methyl, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, silyl ethers and conversion of silyl ethers to other functional groups.
  • Substituted Methyl Ethers include: methoxymethyl, methylthiomethyl, t- utylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p- ethoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacolmethyl, t- butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloro- ethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydro-pyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4- methoxytetrahydrothio-pyranyl, 4-methoxytetrahydrothiothiothio
  • Substituted Ethyl Ethers include: 1-ethoxyethyl, 1-(2,chloroethoxy)ethyl, 1 -methyl- 1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2- fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilyethyl, 2-(phenylselenyl)ethyl, t- butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.
  • Substituted Benzyl Ethers include: p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl ⁇ /-oxido, diphenylmethyl, p, p -dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, ⁇ -naphthyldiphenyl- methyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri-(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxy)phenyldiphenylmethyl, 4,4',4"-ths(
  • Silyl Ethers Silyl ethers include: trimethylsilyl, triethylsilyl, thisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, f-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and f-butylmethoxyphenylsilyl.
  • Esters protecting groups include: esters, carbonates, assisted cleavage, miscellaneous esters, and sulfonates.
  • esters examples include: formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p- chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio) pentanoate, pivaloate, adamantoate,crotonate,4-methoxycrotonate, benzoate, p-phenylbenzoate, and 2,4,6-trimethylbenzoate (mesitoate).
  • Carbonates include: formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p- chlor
  • Carbonates include: methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl) ethyl, 2-(phenylsulfonyl) ethyl, 2-(triphenylphosphonio) ethyl, isobutyl, vinyl, silyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4- dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4- ethoxy-1-naphthyl, and methyl dithiocarbonate.
  • assisted Cleavage protecting groups include: 2-iodobenzoate, 4- azido-butyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl) benzoate, 2- formylbenzene-sulfonate, 2-(methylthiomethoxy) ethyl carbonate, 4- (methylthiomethoxymethyl) benzoate, and 2-(methylthiomethoxymethyl) benzoate.
  • miscellaneous esters include: 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4-(1 ,1 ,3,3-tetramethylbutyl) phenoxyacetate, 2,4-bis(1 ,1-dimethy!propyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (_ ⁇ )-2-methyl-2- butenoate (tigloate), o-(methoxycarbonyl) benzoate, p-P-benzoate, ⁇ - naphthoate, nitrate, alkyl N,N,N ' ⁇ / '-tetramethylphosphorodiamidate, N- phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4- dinitrophenylsulfenate.
  • Protective sulfates includes: sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate.
  • the protection for 1 ,2 and 1 ,3-diols group includes: cyclic acetals and ketals, cyclic ortho esters, and silyl derivatives. Cyclic Acetals and Ketals
  • Cyclic acetals and ketals include: methylene, ethylidene, 1-f-butylethylidene,
  • Cyclic ortho esters include: methoxymethylene, ethoxymethylene, dimethoxy- methylene, 1-methoxyethylidene, 1-ethoxyethylidine, 1 ,2- dimethoxyethylidene, ⁇ -methoxybenzylidene, 1-(N,N- dimethylamino)ethylidene derivative, ⁇ -( ⁇ /, ⁇ /-dimethylamino) benzylidene derivative, and 2-oxacyclopentylidene.
  • Ester protecting groups include: esters, substituted methyl esters, 2- substituted ethyl esters, substituted benzyl esters, silyl esters, activated esters, miscellaneous derivatives, and stannyl esters.
  • Substituted Methyl Esters include: 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxy-methyl, benzyloxymethyl, phenacyl, p-bromophenacyl, ⁇ -methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N- phthalimidomethyl.
  • 2-Substituted Ethyl Esters include: 2,2,2-thchloroethyl, 2-haloethyl, ⁇ - chloroalkyl, 2-(trimethylsily)ethyl, 2-methylthioethyl, 1 ,3-dithianyl-2-methyl, 2(p-nitrophenylsulfenyl)-ethyl, 2-(p-toluenesulfonyl)ethyl, 2-(2'-pyhdyl)ethyl, 2- (diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, f-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4-(trimethylsily)-2-buten-1-yl, cinnamyl, ⁇ - methylcinnamyl, phenyl, p-(methyl
  • Substituted Benzyl esters include: triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5- dibenzo-suberyl, 1 -pyrenylmethyl,2-(trifluoromethyl)-6-chromylmethyl, 2,4,6- trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p- methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl, and 4-P-benzyl.
  • Silyl esters include: trimethylsilyl, triethylsilyl, f-butyldimethylsilyl, / ' - propyldimethylsilyl, phenyldimethylsilyl, and di- .-butylmethylsi ⁇ yl.
  • Miscellaneous Derivatives Miscellaneous derivatives includes: oxazoles, 2-alkyl-1 ,3-oxazolines, 4-alkyl- 5-OXO-1 , 3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group, and pentaaminocobalt(lll) complex.
  • Stannyl Esters Examples of stannyl esters include: triethylstannyl and tri-n-butylstannyl.
  • AMIDES AND HYDRAZIDES include: N,N -dimethyl, pyrrolidinyl, piperidinyl, 5,6- dihydrophenanthridinyl, o-nitroanilides, ⁇ /-7-nitroindolyl, ⁇ /-8-nitro-1 , 2,3,4- tetrahydroquinolyl, and p-P-benzenesulfonamides.
  • Hydrazides include: N- phenyl, N,N '-diisopropyl and other dialkyl hydrazides.
  • Carbamates include: carbamates, substituted ethyl, assisted cleavage, photolytic cleavage, urea-type derivatives, and miscellaneous carbamates.
  • Carbamates include: methyl and ethyl, 9-fluorenylmethyl, 9-(2- sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-_ l -butyl-[9-(1O,10- dioxo-10,10,10,10-tetrahydro- thioxanthyl)]methyl, and 4-methoxyphenacyl.
  • Substituted Ethyl protective groups include: 2,2,2-trichloroethyl, 2- trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1 ,1-dimethyl- 2-haloethyl, 1 ,1dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1- methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-f-butylphenyl)-1-methylethyl, 2-(2'-and 4'-pyridyl)ethyl, 2-( ⁇ /, ⁇ /-icyclohexylcarboxamido)- ethyl, f-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, connamyl, 4-
  • Protection via assisted cleavage includes: 2-methyithioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1 ,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethyl-thiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1 ,1-dimethyl-2cyanoethyl, m-chloro-p- acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolyl-methyl, and 2-(trifluoromethyl)-6-chromonylmethyl.
  • Photolvtic Cleavage Photolvtic cleavage methods use groups such as: m-nitrophenyl, 3,5- dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o- nitrophenyl)methyl.
  • Urea-Type Derivatives examples include: phenothiazinyl-(10)-carbonyl derivative, N '-p-toluenesulfonylaminocarbonyl, and N '- phenylaminothiocarbonyl.
  • miscellaneous carbamates include: f-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxy-benzyl, diisopropylmethyl, 2,2- dimethoxycarbonylvinyl, o-( ⁇ /, ⁇ /-dimethyl-carboxamido)-benzyl, 1 ,1-dimethyl- 3( ⁇ /, ⁇ /-dimethylcarboxamido)propyl, 1 ,1-dimethyl-propynyl, di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p(p - methoxyphenyl- azo)benzyl, 1-methylcyclo
  • Amides includes: ⁇ /-formyl, ⁇ /-acetyl, ⁇ /-chloroacetyl, ⁇ /-trichloroacetyl, ⁇ /-trifluoroacetyl, ⁇ /-phenylacetyl, ⁇ /-3-phenylpropionyl, ⁇ /-picolinoyl, ⁇ /-3- pyridyl-carboxamide, ⁇ /-benzoylphenylalanyl derivative, ⁇ /-benzoyl, and N-p- phenylbenzoyl.
  • Assisted Cleavage Assisted cleavage groups include: ⁇ /-o-nitrophenylacetyl, N-o- nitrophenoxyacetyl, ⁇ /-acetoacetyl, ( ⁇ / -dithiobenzyloxycarbonylamino)acetyl, ⁇ /-3-(p-hydroxphenyl) propionyl, ⁇ /-3-(o-nitrophenyl)propionyl, ⁇ /-2-methyl-2- (o-nitrophenoxy)propionyl, ⁇ /-2-methyl-2-(o-phenylazophenoxy)propionyl, ⁇ /-4- chlorobutyryl, ⁇ /-3-methyl-3-nitrobutyryl, ⁇ /-o-nitrocinnamoyl, N- acetylmethionine derivative, ⁇ /-o-nitrobenzoyl, N-o- (benzoyloxymethyl)benzoyl, and 4,5-diphenyl-3-oxazolin-2
  • Cyclic imide derivatives include: ⁇ /-phthalimide, ⁇ /-dithiasuccinoyl, ⁇ /-2,3-diphenyl-maleoyl, ⁇ /-2,5-dimethylpyrrolyl, ⁇ /-1 ,1 ,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1 ,3-dimethyl-1 ,3,5-triazacyclohexan-2-one, 5-substituted 1 ,3-dibenzyl- 1 ,3,5-triazacyclohexan-2-one, and 1-substituted 3,5-dinitro-4-pyridonyl.
  • Protective groups for - NH include: ⁇ /-alkyl and ⁇ /-aryl amines, imine derivatives, enamine derivatives, and ⁇ /-hetero atom derivatives (such as N- metal, N-N, N-P, N-Si, and N-S), ⁇ /-sulfenyl, and ⁇ /-sulfonyl.
  • ⁇ /-Alkyl and ⁇ /-Aryl Amines ⁇ /-alkyl and ⁇ /-aryl amines include: ⁇ /-methyl, ⁇ /-allyl, ⁇ /-[2-(trimethylsilyl)ethoxyl]-methyl, ⁇ /-3-acetoxypropyl,
  • quaternary ammonium salts ⁇ /-benzyl, ⁇ /-di(4-methoxyphenyl)methyl, ⁇ /-5-dibenzosuberyl, ⁇ /-triphenylmethyl, ⁇ /-(4-methoxyphenyl)diphenylmethyl, ⁇ /-9-phenylfluorenyl, ⁇ /-2,7-dichloro-9-fluorenylmethylene, ⁇ /-ferrocenylmethyl, and ⁇ /-2-picolylamine N '-oxide.
  • Imine derivatives include: ⁇ /-1 ,1-dimethylthiomethylene, ⁇ /-benzylidene, ⁇ /-p-methoxybenzylidene, ⁇ /-diphenylmethylene, ⁇ /-[(2-pyridyl)mesityl]methylene, N-(N ',N '-dimethylaminomethylene), N,N '-isopropylidene, ⁇ /-p-nitrobenzylidene, ⁇ /-salicylidene,
  • ⁇ /-5-chlorosalicylidene ⁇ /-(5-chloro-2-hydroxyphenyl)phenyl-methylene, and ⁇ /-cyclohexylidene.
  • Enamine Derivative An example of an enamine derivative is N- (5,5-dimethyl-3-oxo-1-cyclohexenyl).
  • ⁇ /-Hetero Atom Derivatives ⁇ /-metal derivatives include: ⁇ /-borane derivatives, ⁇ /-diphenylborinic acid derivative, ⁇ /-[phenyl(pentacarbonylchromium- or -tungsten)]carbenyl, and ⁇ /-copper or ⁇ /-zinc chelate.
  • Examples of ⁇ /-/V derivatives include: ⁇ /-nitro, ⁇ /-nitroso, and ⁇ /-oxide.
  • Examples of ⁇ /-P derivatives include: ⁇ /-diphenylphosphinyl, ⁇ /-dimethylthiophosphinyl, ⁇ /-diphenylthiophosphinyl, ⁇ /-dialkyl phosphoryl, ⁇ /-dibenzyl phosphoryl, and ⁇ /-diphenyl phosphoryl.
  • ⁇ /-sulfenyl derivatives include: ⁇ /-benzenesulfenyl, ⁇ /-o-nitrobenzenesulfenyl, ⁇ /-2,4-dinitrobenzenesulfenyl, ⁇ /-pentachlorobenzenesulfenyl, ⁇ /-2-nitro-4-methoxy-benzenesulfenyl, ⁇ /-t phenylmethylsulfenyl, and ⁇ /-3-nitropyridinesulfenyl.
  • ⁇ /-sulfonyl derivatives include: ⁇ /-p-toluenesulfonyl, ⁇ /-benzenesulfonyl, ⁇ /-2,3,6-trimethyl- 4-methoxybenzenesulfonyl, ⁇ /-2,4,6-trimethoxybenzenesulfonyl, ⁇ /-2,6-dimethyl-4-methoxy- benzenesulfonyl, ⁇ /-pentamethylbenzenesulfonyl, ⁇ /-2,3,5,6-tetramethyl-4-methoxybenzene- sulfonyl, ⁇ /-4-methoxybenzenesulfonyl, ⁇ /-2,4,6-trimethylbenzenesulfonyl, ⁇ /-2,6-dimethoxy- 4-methylbenzenesulfonyl, ⁇ /-2,2,5,7,8-pentamethylchroman-6-sulfony
  • Disclosed compounds which are masked or protected may be prodrugs, compounds metabolized or otherwise transformed in vivo to yield a disclosed compound, e.g., transiently during metabolism.
  • This transformation may be a hydrolysis or oxidation which results from contact with a bodily fluid such as blood, or the action of acids, or liver, gastrointestinal, or other enzymes.
  • mice Male Sprague Dawley rats (250-300g), obtained from Bantin and Kingman, (Hull, U.K.) were housed in groups of 3. All animals were kept under a 12h light/dark cycle (lights on at 07h OOmin) with food and water ad libitum. All experiments were carried out by an observer blind to drug treatments.
  • PD 198306 [N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide] and CI-1008 (pregabalin) were synthesized at Parke-Davis (Ann Arbor, Ml, USA). PD 198306 was suspended in cremophor:ethanol:water (1 :1 :8) vehicle. Pregabalin was dissolved in water. Both compounds were administered orally. Streptozocin (Aldrich, UK) was dissolved in 0.9% w/v NaCI and administered intraperitoneally. Drug administrations were made in a volume of 1 ml/kg.
  • mice Male Sprague Dawley rats (250-300g), obtained from Charles River, Margate, U.K.) were housed in groups of 3-6. All animals were kept under a 12h light/dark cycle (lights on at 07h OOmin) with food and water ad libitum. All experiments were carried out by an observer blind to drug treatments.
  • Diabetes was induced in rats by a single i.p. injection of streptozocin (50mg/kg) as described previously (Courteix et al., 1993).
  • Intrathecal injections PD 198306 and pregabalin were administered intrathecally in a volume of 10 ⁇ l using a 100 ⁇ l Hamilton syringe by exposing the spine of the rats under brief isoflurane anaesthesia. Injections were made into the intrathecal space between lumbar region 5-6 with a 10 mm long 27 gauge needle. Penetrations were judged successful if there was a tail flick response. The wound was sealed with an autoclip and rats appeared fully awake within 2-3 min following injection.
  • Static allodynia was assessed with von Frey hairs, before (baseline, BL) and 0.5h, 1h and 2h after intrathecal or intraplantar administration of PD 198306 (1-30 ⁇ g, i.t.), vehicle (cremophor:ethanol:water, 1 :1 :8) or pregabalin (10 ⁇ g, i.t).
  • static allodynia was assessed with von Frey hairs, before (baseline, BL) and 1h after oral administration of PD 198306 (3-30mg/kg, p.o.), vehicle (cremophor:ethanol:water, 1 :1 :8) or pregabalin (30mg/kg, p.o.).
  • Static allodynia was assessed before and 1 h after the morning administration. In the afternoon static allodynia was assessed before, 1h, 2h and 3h after administration for streptozocin treated animals. CCI animals were assessed before, 1 h and 2h after administration
  • PD 198306 and pregabalin were synthesised at Parke-Davis (Ann Arbor, Ml, USA).
  • PD 198306 was suspended in cremophor:ethanol:water (1 :1 :8) vehicle.
  • Pregabalin was dissolved in water. Both compounds were administered orally, intrathecally or intraplantar in volumes of 1 ml/kg, 10 ⁇ l and 100 ⁇ l respectively.
  • Streptozocin (Aldrich, UK) was dissolved in 0.9% w/v NaCI and administered intraperitoneally in a volume of 1 ml/kg.
  • the animals and methods for developing chronic constriction injury in the rat, injecting test compounds, and evaluation of static allodynia were according to Example 2 above.
  • PD219622, PD297447, PD 184352, PD 254552 and pregabalin were administered intrathecally at doses of 30 g for all PD compounds and 100 ⁇ g for pregabalin.
  • Static allodynia was assessed with von Frey hairs, before (baseline, BL) and 0.5h, 1 h and 2h after intrathecal administration of the compounds
  • Drugs used PD297447, PD219622, PD 254552, PD 184352 (CI-1040), and pregabalin were synthesised at Parke-Davis (Ann Arbor, Ml, USA).
  • PD297447, PD219622, PD 254552 and PD 184352 were suspended in cremophor:ethanol:water (1 :1 :8) vehicle.
  • Pregabalin was dissolved in water. All compounds were administered intrathecally in a 10 ⁇ l volume.
  • the antiallodynic effect was only evident for 30min post-injection and thus, shorter than the one observed for pregabalin (100 ⁇ g). The magnitude of the effect was similar for 30 ⁇ g of PD 184352 and 100 ⁇ g of pregabalin.
  • 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 HCI (10%) was added to the concentrate, and the solution was extracted with dichloromethane.
  • the organic phase was dried (MgS04) 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;
  • reaction mixture was concentrated in vacuo to a brown oil that was purified by flash silica chromatography. Elution with dichloromethane ⁇ dichloromethane-methanol (166:1) afforded 0.2284 g of a light-brown viscous oil.
  • 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. HCI (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 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.
  • Examples 3 to 12 and 78 to 102 in the table below were prepared by the general procedures of Examples 1 and 2.
  • Examples 13 to 77 were prepared utilizing combinatorial synthetic methodology by reacting appropriately substituted phenylamino benzoic acids
  • 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 invention compounds are useful in treating chronic pain proliferative diseases by virtue of their selective inhibition of the dual specificity protein kinases MEKi and MEK2.
  • the invention compound has been evaluated in a number of biological assays which are normally utilized to establish inhibition of proteins and kinases, and to measure mitogenic and metabolic responses to such inhibition.
  • reaction temperature was allowed to increase slowly to room temperature, at which temperature it was stirred for 2 days.
  • the reaction mixture was concentrated.
  • Aqueous HCI (10%) was added to the concentrate, and the solution was extracted with dichloromethane.
  • the organic phase was dried (MgSO4) and then boiled over a steambath to low volume and cooled to room temperature.
  • the off-white fibers were collected by vacuum filtration, rinsed with hexanes, and vacuum-oven dried. (76°C; ca.
  • A4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohoW-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.
  • Example 49A The following benzyl alcohols were prepared by the general procedure of Example 49A.
  • 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.
  • 4-ylmethyl-benzamide 80A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- 475 ethyl)-benzamide 81 A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyridin- 445
  • the E_2 ⁇ 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 e Preparation of f4-Chloro-2-(1 H-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)- amine

Abstract

The invention features a method for treating chronic pain using a compound of formula (I) and 1 (A) which are shown in claim 1 and 26 of the application.

Description

METHOD FOR TREATING CHRONIC PAIN USING MEK INHIBITORS
BACKGROUND
The invention features a method for treating chronic pain, using MEK inhibitors. Chronic pain includes neuropathic pain, and chronic inflammatory pain.
Abnormality anywhere in a nerve pathway disrupts nerve signals, which in turn are abnormally interpreted in the brain, causing neuropathic pain. Neuropathic pain may be, for example, a deep ache, a burning sensation, or hypersensitivity to touch. Diseases or conditions associated with neuropathic pain include, without limitation, diabetic neuropathy, causalgia, plexus avulsion, neuroma, vasculitis, crush injury, viral infections (e.g., herpes virus infection or HIV), constriction injury, tissue injury, nerve injury from the periphery to the central nervous system, limb amputation, hypothyroidism, uremia, chronic alcoholism, post-operative pain, arthritis, back pain, and vitamin deficiencies .
Infections such as herpes zoster (shingles) can cause nerve inflammation and produce postherpetic neuralgia, a chronic burning localized to the area of viral infection. Hyperalgesia is when an already noxious stimulus becomes more painful, and allodynia, when a previously non-noxious stimulus becomes painful (such as contact of clothing or a breeze). Reflex sympathetic dystrophy is accompanied by swelling and sweating or changes in local blood flow, tissue atrophy, or osteoporosis. Causalgia, including severe burning pain and swelling, sweating, and changes in blood flow, may follow an injury or disease of a major nerve such as the sciatic nerve. Some types of chronic low back pain can have a neuropathic component (e.g., sciatica, postpoliomyelitis and CPRM). Neuropathic pain may also be induced by cancer or chemotherapy. Neuropathic pain is currently treated with anticonvulsants such as carbamazepine and antidepressants such as amitryptaline. NSAIDS and opioids generally have little effect (Fields et al 1994 Textbook of Pain p 991- 996 (pub: Churchill Livingstone), James & Page 1994 J.Am. Pediatr. Med.Assoc, 8: 439-447, Galer, 1995 Neurology 45 S17-S25. Neuropathic conditions that have been treated with gabapentin include: postherpetic neuralgia, postpoliomyelitis, CPRM, HIV-related neuropathy, trigeminal neuralgia, and reflex sympathetic dystrophy (RSD). The generally weak efficacy of antiinflammatory agents suggests that the mechanism for chronic pain is separate from hyperalgesia.
SUMMARY OF THE INVENTION
The invention features a method for treating chronic pain, which method includes the step of administering a composition including a MEK inhibitor to a patient in need of such treatment. Chronic pain includes neuropathic pain, idiopathic pain, and pain associated with vitamin deficiencies, uremia, hypothyroidism post-operative pain, arthritis, back pain, and chronic alcoholism. The invention also features compounds as disclosed, formulated for the treatment of chronic pain. Such a composition may include one or more MEK inhibitor compounds having a structure disclosed in patent applications PCT/US98/13106, international filing date June 24, 1998, and PCT/US98/13105, international filing date June 24, 1998.
Examples of MEK inhibitors include 4-bromo and 4-iodo phenylamino benzhydroxamic acid derivatives which are kinase inhibitors and as such are useful for treating proliferative diseases such as cancer, psoriasis, and restenosis. The compounds are defined by Formula I
wherein:
Rl is hydrogen, hydroxy, Ci-Cø alkyl, C-i-Cs alkoxy, halo, trifluoromethyl, or CN;
R2 is hydrogen; R3, R4, and R5 independently are hydrogen, hydroxy, halo, trifluoromethyl,
C1-C8 alkyl, C<|-C8 alkoxy, nitro, CN, or (O or NH)m-(CH2)n-R9, where Rg is hydrogen, hydroxy, CO2H or NRιoR1 i ; n is 0 to 4; m is 0 or 1 ; R10 and R-| 1 independently are hydrogen or 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-j-Cg alkyl;
O II
R6 is hydrogen, C-|-C8 alkyl, C-C1-C8 alkyl, aryl, aralkyl, or
C3-C10 cycloalkyl;
R7 is hydrogen, C^-Cg alkyl, C2-C8 alkenyl, C2-C8 alkynyl,
C3-C10 (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NRg); or RQ and R7 taken together with the N-O 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 NRI QRH ; and wherein any of the foregoing alkyl, alkenyl, and alkynyl groups can be unsubstituted or substituted by cycloalkyl (or cycloalkyl optionally containing a heteroatom selected from O, S, or NRg), aryl, aryloxy, heteroaryl, or heteroaryloxy. Preferred compounds have Formula
where R-| , R3, R4, R5, RQ, and R7 are as defined above. Especially preferred are compounds wherein R<| is methyl or halo, and R3, R4, and R5 are halo such as fluoro or bromo.
Another preferred group of compounds have Formula III
O
R, wherein R<| , R3, R4, R5, and R7 are as defined above.
The most preferred compounds are those wherein R-| is methyl or halo such as F, Br, Cl, and I, R3 is hydrogen or halo such as fluoro, R4 is halo such as fluoro, and R5 is hydrogen or halo such as fluoro or bromo. Such compounds have the formulas
O O
Specific compounds provided by the invention include the following:
3,4,5-Trifluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Chloro-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy- benzamide;
N-Hydroxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzamide;
3,4,5-Trifluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide; 5-Chloro-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy- benzamide;
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide;
2-(2-Fluoro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy-benzamide;
5-Chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide;
5-Bromo-2-(2-bromo-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-methyl-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-5-chloro-3,4-difluoro-N-hydroxy- benzamide;
2-(2-Bromo-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide; 3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide;
2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide;
2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-benzamide; N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide;
N-Cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro- benzamide;
N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide; 5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide;
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4-difluoro-benzamide;
N-Cyclopropylmethoxy-2-(2-fluoro-4-iodo-phenylamino)-4-nitro- benzamide;
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4,5-trifluoro- benzamide;
5-Chloro-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4-difluoro-benzamide; 5-Bromo-2-(2-bromo-4-iodo-phenylamino)-N-ethoxy-3,4-difluoro- benzamide;
2-(2-Chloro-4-iodo-phenylamino)-N-ethoxy-4-nitro-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4,5-trifluoro- benzamide;
2-(2-Bromo-4-iodo-phenylamino)-5-chloro-N-cyclopropylmethoxy- 3,4-difluoro-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-nitro- benzamide;
N-Cyclopropylmethoxy-4-fluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide;
N-Cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide;
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro- benzamide;
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;
4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-N-isopropyl- benzamide;
N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-N-methyl- benzamide; 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide;
3,4-Difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide;
2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide (HCI salt);
2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-(tetrahydro-pyran-2-yloxy)- benzamide; 3,4-Difluoro-2-(2-chloro-4-iodo-phenylamino)-N-cyclobutylmethoxy- benzamide;
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N-(2-dimethylamino-ethoxy)- 3,4-difluoro-benzamide monohydrochloride salt; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide;
3,4-Difluoro-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- benzamide;
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4- difluoro-benzamide;
5-Bromo-N-cyclohexylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-N-cyclopentylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; and 5-Bromo-N-cyclobutylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide.
Other aspects of the invention are provided in the description, examples and claims below.
Further examples of MEK inhibitors include 4-bromo and 4-iodo phenylamino benzoic acid derivatives which are selective MEK kinase inhibitors. The compounds are defined by Formula 1(A)
wherein:
R-l is hydrogen, hydroxy, C-i-Cδ alkyl, Ci-Cs alkoxy, halo, trifluoromethyl, or CN;
R2 is hydrogen; R3> R4, and R5 independently are hydrogen, hydroxy, halo, trifluoromethyl, C-i-Cβ alkyl, C<|-C8 alkoxy, nitro, CN, or -(O or NH)m -(CH2)n-Rg, where Rg is hydrogen, hydroxy, CO2H, or NR10R11 ; n is 0-4; m is 0 or 1 ;
Rl0 and R-| 1 independently are hydrogen or C<|-C8 alkyl, or taken together with the nitrogen to which they are attached, can complete a 3-10 member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S, NH, or N-Ci-Cs alkyl; Z is COOR7, tetrazolyl, CONR6R7, CONHNR1 nRl 1 or CH2OR7; RQ and R7 independently are hydrogen, C<|-C8 alkyl, C2-C8 alkenyl,
O
C2-C8 alkynyl, C - Ci-Cs 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 RQ 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, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, and the pharmaceutically acceptable salts thereof. Preferred compounds have Formula ll(A)
where R-| , R3, R4, R5, RQ, and R7 are as defined above. Especially preferred are compounds wherein R-| is methyl or halo, and R3, R4, and R5 are halo such as fluoro or bromo.
The compounds of Formula 11(A) are carboxylic acids when R7 is hydrogen, and are esters when R7 is other than hydrogen. Compounds which are analogous to the acids in physical and biological properties are tetrazolyl derivatives of Formula Ma
Another preferred group of compounds are amides Formula 111(A)
O
I I
R, and hydrazides of Formula Ilia
O
I I
Br or
R,
The benzyl alcohols of the invention have Formula IV(A)
Among this group, the most preferred compounds are those wherein R-l is methyl, R3 is hydrogen or halo such as fluoro, R4 is halo such as fluoro, and R5 is hydrogen or halo such as fluoro, bromo, or chloro. Representative compounds have the formulas
Br or Br or
Br or Preferred embodiments for this invention include methods using one or more of the following compounds: (a) said MEK inhibitor has a structure selected from: 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide; N-Cyclopropylmethoxy-3,4,5-trifuoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Cyclopropylmethoxy-3,4,5-trifuoro-2-(4-iodo-2-methyl-phenylamino)- benzamide, potassium salt;
2-(2-Chloro-4-iodo-phenylamino)-N-cyclobutylmethoxy-3,4-difluoro- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro- benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy- benzamide; 3,4-Difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide; N-Cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-N-cyclobutylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4- difluoro-benzamide; 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide, hydrochloride salt; 5-Bromo-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)- benzamide; 3,4-Difluoro-N-(2-hydroxy-ethoxy)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-(3-hydroxy- propoxy)-benzamide;
2-(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-N-(3-hydroxy-propoxy)- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-N-[2-(2-methoxy- ethoxy)-ethoxy]-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-(3-hydroxy-propoxy)- benzamide; 5-Bromo-3,4-difluoro-N-(3-hydroxy-propoxy)-2-(4-iodo-2-methyl- phenylamino)-benzamide; 3,4,5-Trifluoro-N-(3-hydroxy-propoxy)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
3,4,5-Trifluoro-N-(2-hydroxy-ethoxy)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)- benzamide; and 3,4-Difluoro-N-(2-hydroxy-ethoxy)-2-(4-iodo-2-methyl-phenylamino)- benzamide; (b) said MEK inhibitor has a structure selected from:
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide; N-Cyclopropylmethoxy-3,4,5-trifuoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)- benzamide; 3,4-Difluoro-N-(2-hydroxy-ethoxy)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
(c) said MEK inhibitor has a structure selected from:
2-(2-Chloro-4-iodo-phenylamino)-3,4difluoro-benzoic acid; 3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-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; 2-(2-Chloro-4-iodo-pyenylamino)-3,4-difluoro-5-nitro-benzoic acid; 2-(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-benzoic acid;
7-Fluoro-6-(4-iodo-2-methyl-phenylamino)1 H-benzoimidazole-5- carboxylic acid cyclopropylmethoxy-amide; 5-Chloro-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; and 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid; and
(d) said MEK inhibitor has a structure selected from:
2-(2-Chloro-4-iodo-phenylamino)-3,4difluoro-benzoic acid; and 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)1 H-benzoimidazole-5- carboxylic acid cyclopropylmethoxy-amide.
This invention also provides pharmaceutical formulations adapted for the treatment of chronic pain, said formalities comprising a disclosed compound together with a pharmaceutically acceptable excipient, diluent, or carrier. Preferred formulations include any of the foregoing preferred compounds together with an excipient, diluent, or carrier.
The disclosed compounds are potent and selective inhibitors of kinase enzymes, particularly MEK-| and MEK2. BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is a bar graph representing the paw withdrawal threshold (PWT) in grams as a function of time in days. The empty, cross-hatched, and single- hatched bars are vehicle, PD 198306, and pregabalin, respectively. The arrows indicate time of drug administration (30 mg/kg, p.o.).
FIG 2. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days. Baseline (BL) measurements were taken before treatment. Animals received a single p.o. administration of PD 198306 (3-30mg/kg), or pregabalin (30mg/kg) and withdrawal thresholds were re-assessed 1h after treatment. Treatments were repeated twice a day for two days. Results are expressed median ± 1st and 3rd quartiles. *P<0.05, **P<0.01 , ***P<0.001 significantly different from vehicle treated animals (Mann-Whitney t test; n=7-8).
FIG. 3. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days. Baseline (BL) measurements were taken before treatment. Animals received a single p.o. administration of PD 198306 (3-30mg/kg), or pregabalin
(30mg/kg) and withdrawal thresholds were re-assessed 1h after treatment. Treatments were repeated twice a day for two days. Results are expressed median ± 1st and 3rd quartiles. **P<0.01 significantly different from vehicle treated animals (Mann-Whitney t test; n=6).
FIG. 4. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days. Baseline (BL) measurements were taken before treatment. Animals received a single i.t. administration of PD 198306 (1-30μg/10μl), or pregabalin (100μg/1 Oμl) and withdrawal thresholds were re-assessed at 30min, 1 h and 2h after treatment. Results are expressed median ± 1st and 3rd quartiles. *P<0.05, ***P<0.001 significantly different from vehicle treated animals (Mann- Whitney t test; n=7-9). FIG. 5. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days. Baseline (BL) measurements were taken before treatment. Animals received a single i.t. administration of PD 198306 (1-30μg/10μl), or pregabalin
(100μg/10μl) and withdrawal thresholds were re-assessed at 30min, 1h and 2h after treatment. Results are expressed median ± 1st and 3rd quartiles. *P<0.05, **P<0.01 , ***P<0.001 significantly different from vehicle treated animals (Mann-Whitney t test; n=6-8).
FIG. 6 is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days . Animals received a single intraplantar (i.pl.) administration of PD 198306 (3mg/100μl), or an intrathecal injection of PD 198306 (30μg/10μl) and withdrawal thresholds were re-assessed 1 h after treatment. Results are expressed median ± 1st and 3rd quartiles. **P<0.01 significantly different from vehicle treated animals (Mann-Whitney t test; n=6-9).
FIG. 7. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days. Animals received a single intraplantar (i.pl.) administration of PD 198306 (3mg/100μl), or an intrathecal injection of PD 198306 (30μg/10μl) and withdrawal thresholds were re-assessed 1 h after treatment. Results are expressed median ± 1st and 3rd quartiles. **P<0.01 significantly different from vehicle treated animals (Mann-Whitney t test; n=6).
FIG. 8 is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments. Baseline (BL) measurements were taken before treatment. Animals received a single i.t. administration of PD219622, PD297447, PD 184352, or PD 254552 (30μg/10μl), or pregabalin (100μg/10μl) and withdrawal thresholds were re-assessed at 30min, 1 h and 2h after treatment. Results are expressed median ± 1st and 3rd quartiles. *P<0.05, **P<0.01 , ***P<0.001 significantly different from vehicle treated animals (Mann-Whitney t test; n=7-8).
DETAILED DESCRIPTION The compounds disclosed herein are pharmaceutically active, for example, they inhibit MEK. MEK enzymes are dual specificity kinases involved in, for example, immunomodulation, inflammation, and proliferative diseases such as cancer and restenosis, as well as pair.
Proliferative diseases are caused by a defect in the intracellular signaling system, or the signal transduction mechanism of certain proteins. Defects include a change either in the intrinsic activity or in the cellular concentration of one or more signaling proteins in the signaling cascade . The cell may produce a growth factor that binds to its own receptors, resulting in an autocrine loop, which continually stimulates proliferation. Mutations or overexpression of intracellular signaling proteins can lead to spurious mitogenic signals within the cell. Some of the most common mutations occur in genes encoding the protein known as Ras, a G-protein that is activated when bound to GTP, and inactivated when bound to GDP. The above- mentioned growth factor receptors, and many other mitogenic receptors, when activated, lead to Ras being converted from the GDP-bound state to the GTP- bound state. This signal is an absolute prerequisite for proliferation in most cell types. Defects in this signaling system, especially in the deactivation of the Ras-GTP complex, are common in cancers, and lead to the signaling cascade below Ras being chronically activated.
Activated Ras leads in turn to the activation of a cascade of serine/threonine kinases. One of the groups of kinases known to require an active Ras-GTP for its own activation is the Raf family. These in turn activate MEK (e.g., MEKi and MEK2) which then activates MAP kinase, ERK (ERKT and ERK2). Activation of MAP kinase by mitogens appears to be essential for proliferation; constitutive activation of this kinase is sufficient to induce cellular transformation. Blockade of downstream Ras signaling, for example by use of a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants. Although Ras is not itself a protein kinase, it participates in the activation of Raf and other kinases, most likely through a phosphorylation mechanism. Once activated, Raf and other kinases phosphorylate MEK on two closely adjacent serine residues, s218 anc| s222 jn the case of MEK-1 , which are the prerequisite for activation of MEK as a kinase. MEK in turn phosphorylates MAP kinase on both a tyrosine, γ185 anc| a threonine residue, T183 separated by a single amino acid.
This double phosphorylation activates MAP kinase at least 100-fold. Activated MAP kinase can then catalyze the phosphorylation of a large number of proteins, including several transcription factors and other kinases. Many of these MAP kinase phosphorylations are mitogenically activating for the target protein, such as a kinase, a transcription factor, or another cellular protein. In addition to Raf-1 and MEKK, other kinases activate MEK, and MEK itself appears to be a signal integrating kinase. Current understanding is that MEK is highly specific for the phosphorylation of MAP kinase. In fact, no substrate for MEK other than the MAP kinase , ERK, has been demonstrated to date and MEK does not phosphorylate peptides based on the MAP kinase phosphorylation sequence, or even phosphorylate denatured MAP kinase. MEK also appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK may require a prior strong interaction between the two proteins. Both this requirement and the unusual specificity of MEK are suggestive that it may have enough difference in its mechanism of action to other protein kinases that selective inhibitors of MEK, possibly operating through allosteric mechanisms rather than through the usual blockade of the ATP binding site, may be found. The effect of the MEK inhibitor PD 198306 has been investigated in two animal models of neuropathic pain by assessing static allodynia with von Frey hairs.
Oral administration of PD 198306 (3-30mg/kg) had no effect in the model of chronic constriction injury of the sciatic nerve (CCI). However, after repeated administration (3 doses over two days) it had a transient effect in the diabetic neuropathy model (streptozocin). This may be due to disorders of the blood- brain barrier induced by the diabetic condition in these animals, thus allowing central action of the compound. Intrathecal administration of PD 198306 (1- 30μg) dose-dependently blocked static allodynia in both the streptozocin and the
CCI models of neuropathic pain, with minimum effective doses (MED) of 3 and
10μg respectively. The highest dose used (30μg) totally blocked the maintenance of static allodynia, for up to 1h. Intraplantar administration of PD 198306 (3mg/100μl) at a dose 100-fold higher than the dose shown to be effective intrathecally (30μg/10μl) had no effect on static allodynia in either of the neuropathic pain models. This finding confirms the lack of effect seen after systemic administration and suggests a central site of action for the compound.
This study supports the use of MEK inhibitors as potential new therapeutic tools for chronic pain. The study of potential side-effects, especially related to memory, of future brain-penetrant MEK inhibitors will further support the therapeutic window for this novel class of compounds in the treatment of pain.
A. Terms
Certain terms are defined below and by their usage throughout this disclosure.
Alkyl groups include aliphatic (i.e., hydrocarbyl or hydrocarbon radical structures containing hydrogen and carbon atoms) with a free valence. Alkyl groups are understood to include straight chain and branched structures. Examples include methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, t- butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl, 2,3-dimethylhexyl, 1 ,1- dimethylpentyl, heptyl, and octyl. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
Alkyl groups can be substituted with 1 , 2, 3 or more substituents which are independently selected from halo (fluoro, chloro, bromo, or iodo), hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical)oxy. Specific examples include fluoromethyl, hydroxyethyl, 2,3-dihydroxyethyl, (2- or 3-furanyl)methyl, cyclopropylmethyl, benzyloxyethyl, (3-pyridinyl)methyl, (2- or 3-furanyl)methyl, (2-thienyl)ethyl, hydroxypropyl, aminocyclohexyl, 2-dimethylaminobutyl, methoxymethyl, Λ/-pyridinylethyl, diethylaminoethyl, and cyclobutylmethyl. Alkenyl groups are analogous to alkyl groups, but have at least one double bond (two adjacent sp2 carbon atoms). Depending on the placement of a double bond and substituents, if any, the geometry of the double bond may be entgegen (E), or zusammen (Z), cis, or trans. Similarly, alkynyl groups have at least one triple bond (two adjacent sp carbon atoms). Unsaturated alkenyl or alkynyl groups may have one or more double or triple bonds, respectively, or a mixture thereof; like alkyl groups, unsaturated groups may be straight chain or branched, and they may be substituted as described both above for alkyl groups and throughout the disclosure by example. Examples of alkenyls, alkynyls, and substituted forms include cis-2-butenyl, trans-2-butenyl, 3-butynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 3-methyl(5-phenyl)-4-pentynyl, 2-hydroxy-2-propynyl, 2-methyl-2-propynyl, 2- propenyl, 4-hydroxy-3-butynyl, 3-(3-fluorophenyl)-2-propynyl, and 2-methyl-2- propenyl. In formula (I), alkenyls and alkynyls can be C 2- or C 2_8, for example, and are preferably C 3.4 or C 3.8- More general forms of substituted hydrocarbon radicals include hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, and corresponding forms for the prefixes amino-, halo- (e.g., fluoro-, chloro-, or bromo-), nitro-, alkyl-, phenyl-, cycloalkyl- and so on, or combinations of substituents. According to formula (I), therefore, substituted alkyls include hydroxyalkyl, aminoalkyl, nitroalkyl, haloalkyl, alkylalkyl (branched alkyls, such as methylpentyl), (cycloalkyl)alkyl, phenylalkyl, alkoxy, alkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, (heterocyclic radical)alkyl, and (heterocyclic radical)oxyalkyl. Ri thus includes hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocycloalkyl, aminoaryl, alkylalkenyl, (alkylaryl)alkyl, (haloaryl)alkyl, (hydroxyaryl)alkynyl, and so forth. Similarly, RA includes hydroxyalkyl and aminoaryl, and RB includes hydroxyalkyl, aminoalkyl, and hydroxyalkyl(heterocyclic radical)alkyl. Heterocyclic radicals, which include but are not limited to heteroaryls, include: furyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, pyrrolyl, imidazolyl, 1 ,3,4-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, and their nonaromatic counterparts. Further examples of heterocyclic radicals include piperidyl, quinolyl, isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyrrolyl, pyrrolidinyl, octahydroindolyl, octahydrobenzothiofuranyl, and octahydrobenzofuranyl.
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 IC5o for one of the above-named other enzymes. Preferably, a selective inhibitor has an IC5o that is at least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/5000, or less than that of its ICso or one or more of the above-named enzymes. B. Compounds
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, or amino. 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, triazolyl, thiazolyl, xanthenyl, pyronyl, indolyl, pyrimidyl, naphthyridyl, pyridyl, 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, or amino. 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 "C-i-Cs alkyl" means straight and branched chain aliphatic groups having from one to eight carbon atoms. Typical C-|-C8 alkyl groups include methyl, ethyl, isopropyl, tert.-butyl, 2,3-dimethylhexyl, and 1 ,1-dimethylpentyl. The alkyl groups can be unsubstituted or substituted by cycloalkyl, cycloalkyl containing a heteroatom selected from O, S, or NRg, aryl, aryloxy, heteroaryl, or heteroaryloxy, as those terms are defined above. Examples of aryl and aryloxy substituted alkyl groups include phenylmethyl, 2-phenylethyl, 3-chlorophenylmethyl, 1 ,1-dimethyl-3-(2-nitrophenoxy)butyl, and 3,4,5-trifluoronaphthylmethyl. Examples of alkyl groups substituted by a heteroaryl or heteroaryloxy group include thienylmethyl, 2-furylethyl, 6-furyloxyoctyl, 4-methylquinolyloxymethyl, and 6-isothiazolylhexyl. Cycloalkyl substituted alkyl groups include cyclopropylmethyl, 2-cyclopentylethyl, 2-piperidin-1 -ylethyl, 3-(tetrahydropyran-2-yl)propyl, and cyclobutylmethyl. "C2"Cδ 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 aryl, aryloxy, heteroaryl, or heteroyloxy, for example 3-phenylprop-2-enyl, 6-thienyl-hex-2-enyl, 2-furyloxy- but-2-enyl, and 4-naphthyloxy-hex-2-enyl.
"C2-C8 Alkynyl" means a straight or branched carbon chain having from two to eight carbon atoms and 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 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 "C3-C-10 cycloalkyl" means a non-aromatic ring or fused rings containing from three to ten carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopenyl, cyclooctyl, bicycloheptyl, adamantyl, and cyclohexyl. The ring can optionally contain a heteroatom selected from O, S, or NRg.
Such groups include tetrahydrofuryl, tetrahydropyrrolyl, octahydrobenzofuranyl, octahydroindolyl, and octahydrobenzothiofuranyl. R3, R4, and R5 can include groups defined by the term (O or NH)m-
(CH2)n-R9- Examples of such groups are aminomethyl, 2-aminoethyl, 2-aminoethylamino, 3-aminopropoxy, N,N-diethylamino, 3-(N-methyl-N- isopropylamino)-propylamino, 2-(N-acetylamino)-ethoxy, 4-(N- dimethylaminocarbonylamino)-butoxy, and 3-(N-cyclopropylamino)-propoxy. 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, methyϊthienyl, 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 "C-|-C8 alkyl" means straight and branched chain aliphatic groups having from one to eight carbon atoms, preferably one to four. Typical C-|-C8 alkyl groups include methyl, ethyl, isopropyl, tert.-butyl,
2,3-dimethylhexyl, and 1 ,1-dimethylpentyl. The alkyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, as those terms are defined herein. Typical substituted alkyl groups include chloromethyl, 3-hydroxypropyl, 2-dimethylaminobutyl, and 2-(hydroxymethylamino)ethyl. Examples of aryl and aryloxy substituted alkyl groups include phenylmethyl, 2-phenylethyl, 3-chlorophenylmethyl, 1 ,1-dimethyl-3-(2-nitrophenoxy)butyl, and 3,4,5-trifluoronaphthylmethyl. Examples of alkyl groups substituted by a heteroaryl or heteroaryloxy group include thienylmethyl, 2-furylethyl, 6-furyloxyoctyl, 4-methylquinolyloxymethyl, and 6-isothiazolylhexyl. Cycloalkyl substituted alkyl groups include cyclopropylmethyl, 2-cyclohexyethyl, piperidyl-2-methyl, 2-(piperidin-1-yl)- ethyl, 3-(morpholin-4-yl)propyl.
"C2-C8 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. "C2-C8 Alkynyl" means a straight or branched carbon chain having from two to eight carbon atoms and 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 "C3-C-10 cycloalkyl" means a nonaromatic ring or fused rings containing from three to ten carbon atoms. 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 NRg. Such groups include tetrahydrofuryl, tetrahydropyrrolyl, octahydrobenzofuranyl, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, octahydroindolyl, and octahydrobenzothiofuranyl. The cycloalkyl groups can be substituted with the same substituents as an alkyl and alkenyl groups, for example, halo, hydroxy, aryl, and heteroaryloxy. Examples include 3-hydroxycyclohexyl, 2-aminocyclopropyl, 2-phenylpyrrolidinyl, and 3-thienylmorpholine-1-yl. Rg and R7 can be taken together with the nitrogen to which they are attached to complete a cyclic ring having from 3 to 10 members, which may contain 1 , 2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl. Examples of such cyclic rings include piperazinyl, piperidyl, pyrrolidinyl, morpholino, N-methylpiperazinyl, aziridynyl, and the like. Such rings can be substituted with halo, hydroxy, alkyl, alkoxy, amino, alkyl, and dialkylamino, aryl, aryloxy, heteroaryl, and heteroaryloxy. Typical examples include 3-hydroxy-pyrrolidinyl, 2-fluoro-pipehndyl, 4-(2-hydroxyethyl)-piperidinyl, and 3-thienylmorpholino.
C. Synthesis
The 4-bromo and 4-iodo phenylamino benzhydroxamic 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 phenylamino benzoic acid, and then reacting the benzoic acid phenylamino derivative with a hydroxylamine derivative. This process is depicted in Scheme 1.
Scheme 1
O
*
I 6
HN - O — R^
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 the aniline derivative 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 HNRβOR7 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-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 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 2.
Scheme 2
where L is a leaving group. The general reaction conditions for both of the steps in Scheme 2 are the same as those described above for Scheme 1.
Yet another method for making invention compounds comprises reacting a phenylamino benzhydroxamic acid with an ester forming group as depicted in Scheme 3. Scheme 3
base
where L is a leaving group such as halo, and a base is triethylamine or diisopropylamine. The synthesis of invention compounds of Formula I is further illustrated by the following detailed examples numbers 1 to 102.
The 2-(4-bromo and 4-iodo phenylamino)-benzoic acid derivatives of Formula 1(A) can be prepared from commercially available starting materials utilizing synthetic methodologies well-known to those skilled in organic chemistry and illustrated in synthetic examples 1A - 224A below. 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 (A).
Scheme 1 (A)
O
base
where L is a leaving group, for example halo such as fluoro.
The reaction of aniline and the benzoic acid derivative generally is accomplished by mixing the benzoic acid with an equimolar quantity or excess of the aniline in an unreactive organic solvent such as tetrahydrofuran or toluene, in the presence of a base such as lithium diisopropylamide, n-butyl lithium, sodium hydride, triethylamine, and Hunig's base. The reaction generally is carried out at a temperature of about -78°C to about 100°C, and normally is complete within about 2 hours to about 4 days. The product can be isolated by removing the solvent, for example by evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation. The 2-(phenylamino)-benzoic acid (eg, Formula IA, 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 l(A) 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 = CONHNR-ifjRn) are similarly prepared by coupling a benzoic acid with a hydrazine of the formula H2HNR10F.I I -
The benzyl alcohols of the invention, compounds of Formula l(A) where Z is CH2θRβ and RQ is hydrogen, are readily prepared by reduction of the corresponding benzoic acid according to the following scheme
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 1A to 224A illustrate specific compounds provided by this invention.
D. Uses
The disclosed compositions are useful as both prophylactic and therapeutic treatments for diseases or conditions relating to chronic pain, including neuropathic pain, as provided in the Summary section, as well as diseases or conditions modulated by the MEK cascade. For example, in one embodiment, the disclosed method relates to postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, crush injury, constriction injury, tissue injury, post-surgical pain, arthritis pain, or limb amputation
For example, local injuries can be treated with local or topical administration. Chronic pain affecting the entire body, such as diabetic neuropathy can be treated with systemic administration (injection or orally) of a disclosed composition. Treatment for chronic pain (e.g., post-operative pain) confined to the lower body can be administered centrally, e.g., epidurally. Formulations and methods of administration can include the use of more than one MEK inhibitor, or a combination of a MEK inhibitor and another pharmaceutical agent, such as an anti-inflammatory, analgesic, muscle relaxing, or anti-infective agent. Preferred routes of administration are oral, intrathecal or epidural, subcutaneous, intravenous, intramuscular, and, for non-human mammals, intraplantar, and are preferably epidural.
1. Dosages
Those skilled in the art will be able to determine, according to known methods, the appropriate dosage for a patient, taking into account factors such as age, weight, general health, the type of pain requiring treatment, and the presence of other medications. In general, an effective amount will be between 0.1 and 1000 mg/kg per day, preferably between 1 and 300 mg/kg body weight, and daily dosages will be between 10 and 5000 mg for an adult subject of normal weight. Commercially available capsules or other formulations (such as liquids and film-coated tablets) of 100 mg, 200 mg, 300 mg, or 400 mg can be administered according to the disclosed methods.
2. Formulations
Dosage unit forms include tablets, capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted for subdivision into individual doses.
Dosage unit forms can also be adapted for various methods of administration, including controlled release formulations, such as subcutaneous implants.
Administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intrape toneal, intravesical, local (drops, powders, ointments, gels, or cream), and by inhalation (a buccal or nasal spray).
Parenteral formulations include pharmaceutically acceptable aqueous or nonaqueous solutions, dispersion, suspensions, emulsions, and sterile powders for the preparation thereof. Examples of carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils, and injectable organic esters such as ethyl oleate. Fluidity can be maintained by the use of a coating such as lecithin, a surfactant, or maintaining appropriate particle size. Carriers for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrating agents, (e) solution retarders, (f) absorption acccelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and 0) propellants.
Compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents; antimicrobial agents such as parabens, chlorobutanol, phenol, and sorbic acid; isotonic agents such as a sugar or sodium chloride; absorption-prolonging agents such as aluminum monostearate and gelatin; and absorption-enhancing agents.
3. Related compounds
The invention provides the disclosed compounds and closely related, pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, hydrates or solvated forms thereof; masked or protected forms; and racemic mixtures, or enantiomerically or optically pure forms. Pharmaceutically acceptable salts, esters, and amides include carboxylate salts (e.g., C ι-8 alkyl, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclic), amino acid addition salts, esters, and amides which are within a reasonable benefit/risk ratio, pharmacologically effective, and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Representative salts include 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 laurylsulfonate. These may include alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine. See, for example, S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19 which is incorporated herein by reference. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C ι-6 alkyl amines and secondary di (C ι_6 alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, C 1.3 alkyl primary amines, and di (C ι-2 alkyl)amines. Representative pharmaceutically acceptable esters of the invention include C ι-7 alkyl, C 5-7 cycloalkyl, phenyl, and phenyl(C .-βjalkyl esters. Preferred esters include methyl esters. The invention also includes disclosed compounds having one or more functional groups (e.g., hydroxyl, amino, or carboxyl) masked by a protecting group. Some of these masked or protected compounds are pharmaceutically acceptable; others will be useful as intermediates. Synthetic intermediates and processes disclosed herein, and minor modifications thereof, are also within the scope of the invention. HYDROXYL PROTECTING GROUPS
Hydroxyl protecting groups include: ethers, esters, and protection for 1 ,2- and 1 ,3-diols. The ether protecting groups include: methyl, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, silyl ethers and conversion of silyl ethers to other functional groups. Substituted Methyl Ethers Substituted methyl ethers include: methoxymethyl, methylthiomethyl, t- utylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p- ethoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacolmethyl, t- butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloro- ethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydro-pyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4- methoxytetrahydrothio-pyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, 1 ,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, and 2,3,3a,4,5,6,7,7a-octahydro- 7,8,8-trimethyl-4,7-ethanobenzofuran-2-yl.
Substituted Ethyl Ethers Substituted ethyl ethers include: 1-ethoxyethyl, 1-(2,chloroethoxy)ethyl, 1 -methyl- 1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2- fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilyethyl, 2-(phenylselenyl)ethyl, t- butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.
Substituted Benzyl Ethers Substituted benzyl ethers include: p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl Λ/-oxido, diphenylmethyl, p, p -dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenyl- methyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri-(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxy)phenyldiphenylmethyl, 4,4',4"-ths(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"- tris(levulinoyloxyphenyl) methyl, 4,4',4"tris(benzoyloxyphenyl)methyl, 3- (imidazol-1 -ylmethyl)bis(4',4"-dimethoxyphenyl)-methyl, 1 , 1 -bis(4- methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl) xanthenyl, 9-(9- phenyl-10-oxo) anthryl, 1 ,3-benzodithiolan-2-yl, and benzisothiazolyl S,S- dioxido.
Silyl Ethers Silyl ethers include: trimethylsilyl, triethylsilyl, thisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, f-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and f-butylmethoxyphenylsilyl.
ESTERS Esters protecting groups include: esters, carbonates, assisted cleavage, miscellaneous esters, and sulfonates.
Esters Examples of protective esters include: formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p- chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio) pentanoate, pivaloate, adamantoate,crotonate,4-methoxycrotonate, benzoate, p-phenylbenzoate, and 2,4,6-trimethylbenzoate (mesitoate). Carbonates
Carbonates include: methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl) ethyl, 2-(phenylsulfonyl) ethyl, 2-(triphenylphosphonio) ethyl, isobutyl, vinyl, silyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4- dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4- ethoxy-1-naphthyl, and methyl dithiocarbonate. Assisted Cleavage Examples of assisted cleavage protecting groups include: 2-iodobenzoate, 4- azido-butyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl) benzoate, 2- formylbenzene-sulfonate, 2-(methylthiomethoxy) ethyl carbonate, 4- (methylthiomethoxymethyl) benzoate, and 2-(methylthiomethoxymethyl) benzoate. Miscellaneous Esters In addition to the above classes, miscellaneous esters include: 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4-(1 ,1 ,3,3-tetramethylbutyl) phenoxyacetate, 2,4-bis(1 ,1-dimethy!propyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (_Ξ)-2-methyl-2- butenoate (tigloate), o-(methoxycarbonyl) benzoate, p-P-benzoate, α- naphthoate, nitrate, alkyl N,N,N ' Λ/ '-tetramethylphosphorodiamidate, N- phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4- dinitrophenylsulfenate. Sulfonates
Protective sulfates includes: sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate.
PROTECTION FOR 1.2- AND 1.3-DIOLS The protection for 1 ,2 and 1 ,3-diols group includes: cyclic acetals and ketals, cyclic ortho esters, and silyl derivatives. Cyclic Acetals and Ketals
Cyclic acetals and ketals include: methylene, ethylidene, 1-f-butylethylidene,
1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4- dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and 2-nitrobenzylidene. Cyclic Ortho Esters
Cyclic ortho esters include: methoxymethylene, ethoxymethylene, dimethoxy- methylene, 1-methoxyethylidene, 1-ethoxyethylidine, 1 ,2- dimethoxyethylidene, α-methoxybenzylidene, 1-(N,N- dimethylamino)ethylidene derivative, α-(Λ/,Λ/-dimethylamino) benzylidene derivative, and 2-oxacyclopentylidene. PROTECTION FOR THE CARBOXYL GROUP
ESTERS Ester protecting groups include: esters, substituted methyl esters, 2- substituted ethyl esters, substituted benzyl esters, silyl esters, activated esters, miscellaneous derivatives, and stannyl esters. Substituted Methyl Esters Substituted methyl esters include: 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxy-methyl, benzyloxymethyl, phenacyl, p-bromophenacyl, α-methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N- phthalimidomethyl.
2-Substituted Ethyl Esters 2-Substituted ethyl esters include: 2,2,2-thchloroethyl, 2-haloethyl, α- chloroalkyl, 2-(trimethylsily)ethyl, 2-methylthioethyl, 1 ,3-dithianyl-2-methyl, 2(p-nitrophenylsulfenyl)-ethyl, 2-(p-toluenesulfonyl)ethyl, 2-(2'-pyhdyl)ethyl, 2- (diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, f-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4-(trimethylsily)-2-buten-1-yl, cinnamyl, α- methylcinnamyl, phenyl, p-(methylmercapto)-phenyl, and benzyl. Substituted Benzyl Esters Substituted benzyl esters include: triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5- dibenzo-suberyl, 1 -pyrenylmethyl,2-(trifluoromethyl)-6-chromylmethyl, 2,4,6- trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p- methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl, and 4-P-benzyl. Silyl Esters Silyl esters include: trimethylsilyl, triethylsilyl, f-butyldimethylsilyl, /'- propyldimethylsilyl, phenyldimethylsilyl, and di- .-butylmethylsiϊyl. Miscellaneous Derivatives Miscellaneous derivatives includes: oxazoles, 2-alkyl-1 ,3-oxazolines, 4-alkyl- 5-OXO-1 , 3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group, and pentaaminocobalt(lll) complex. Stannyl Esters Examples of stannyl esters include: triethylstannyl and tri-n-butylstannyl.
AMIDES AND HYDRAZIDES Amides include: N,N -dimethyl, pyrrolidinyl, piperidinyl, 5,6- dihydrophenanthridinyl, o-nitroanilides, Λ/-7-nitroindolyl, Λ/-8-nitro-1 , 2,3,4- tetrahydroquinolyl, and p-P-benzenesulfonamides. Hydrazides include: N- phenyl, N,N '-diisopropyl and other dialkyl hydrazides.
PROTECTION FOR THE AMINO GROUP
CARBAMATES
Carbamates include: carbamates, substituted ethyl, assisted cleavage, photolytic cleavage, urea-type derivatives, and miscellaneous carbamates. Carbamates
Carbamates include: methyl and ethyl, 9-fluorenylmethyl, 9-(2- sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-_l-butyl-[9-(1O,10- dioxo-10,10,10,10-tetrahydro- thioxanthyl)]methyl, and 4-methoxyphenacyl. Substituted Ethyl Substituted ethyl protective groups include: 2,2,2-trichloroethyl, 2- trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1 ,1-dimethyl- 2-haloethyl, 1 ,1dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1- methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-f-butylphenyl)-1-methylethyl, 2-(2'-and 4'-pyridyl)ethyl, 2-(Λ/,Λ/-icyclohexylcarboxamido)- ethyl, f-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, connamyl, 4-nitrocinnamyl, quinolyl, N- hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p- bromobenzyl, p-chlorobenzyl, 2,4dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, and diphenylmethyl.
Assisted Cleavage
Protection via assisted cleavage includes: 2-methyithioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1 ,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethyl-thiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1 ,1-dimethyl-2cyanoethyl, m-chloro-p- acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolyl-methyl, and 2-(trifluoromethyl)-6-chromonylmethyl. Photolvtic Cleavage Photolvtic cleavage methods use groups such as: m-nitrophenyl, 3,5- dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o- nitrophenyl)methyl.
Urea-Type Derivatives Examples of of urea-type derivatives include: phenothiazinyl-(10)-carbonyl derivative, N '-p-toluenesulfonylaminocarbonyl, and N '- phenylaminothiocarbonyl.
Miscellaneous Carbamates In addition to the above, miscellaneous carbamates include: f-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxy-benzyl, diisopropylmethyl, 2,2- dimethoxycarbonylvinyl, o-(Λ/,Λ/-dimethyl-carboxamido)-benzyl, 1 ,1-dimethyl- 3(Λ/,Λ/-dimethylcarboxamido)propyl, 1 ,1-dimethyl-propynyl, di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p(p - methoxyphenyl- azo)benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1- methyl- 1-cyclopropyl- methyl, 1-methyl-(3,5-dimethoxyphenyl)ethyl, 1-methyl- 1 (p-henylazophenyl)- ethyl, 1-methyl-1-phenylethyl, 1-methyl-1-(4- pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri- -butylphenyl, 4- (trimethylammonium) benzyl, and 2,4,6-trimethylbenzyl.
AMIDES
Amides Amides includes: Λ/-formyl, Λ/-acetyl, Λ/-chloroacetyl, Λ/-trichloroacetyl, Λ/-trifluoroacetyl, Λ/-phenylacetyl, Λ/-3-phenylpropionyl, Λ/-picolinoyl, Λ/-3- pyridyl-carboxamide, Λ/-benzoylphenylalanyl derivative, Λ/-benzoyl, and N-p- phenylbenzoyl.
Assisted Cleavage Assisted cleavage groups include: Λ/-o-nitrophenylacetyl, N-o- nitrophenoxyacetyl, Λ/-acetoacetyl, (Λ/ -dithiobenzyloxycarbonylamino)acetyl, Λ/-3-(p-hydroxphenyl) propionyl, Λ/-3-(o-nitrophenyl)propionyl, Λ/-2-methyl-2- (o-nitrophenoxy)propionyl, Λ/-2-methyl-2-(o-phenylazophenoxy)propionyl, Λ/-4- chlorobutyryl, Λ/-3-methyl-3-nitrobutyryl, Λ/-o-nitrocinnamoyl, N- acetylmethionine derivative, Λ/-o-nitrobenzoyl, N-o- (benzoyloxymethyl)benzoyl, and 4,5-diphenyl-3-oxazolin-2-one. Cyclic Imide Derivatives Cyclic imide derivatives include: Λ/-phthalimide, Λ/-dithiasuccinoyl, Λ/-2,3-diphenyl-maleoyl, Λ/-2,5-dimethylpyrrolyl, Λ/-1 ,1 ,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1 ,3-dimethyl-1 ,3,5-triazacyclohexan-2-one, 5-substituted 1 ,3-dibenzyl- 1 ,3,5-triazacyclohexan-2-one, and 1-substituted 3,5-dinitro-4-pyridonyl.
SPECIAL -NH PROTECTIVE GROUPS
Protective groups for - NH include: Λ/-alkyl and Λ/-aryl amines, imine derivatives, enamine derivatives, and Λ/-hetero atom derivatives (such as N- metal, N-N, N-P, N-Si, and N-S), Λ/-sulfenyl, and Λ/-sulfonyl.
Λ/-Alkyl and Λ/-Aryl Amines Λ/-alkyl and Λ/-aryl amines include: Λ/-methyl, Λ/-allyl, Λ/-[2-(trimethylsilyl)ethoxyl]-methyl, Λ/-3-acetoxypropyl,
Λ/-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, Λ/-benzyl, Λ/-di(4-methoxyphenyl)methyl, Λ/-5-dibenzosuberyl, Λ/-triphenylmethyl, Λ/-(4-methoxyphenyl)diphenylmethyl, Λ/-9-phenylfluorenyl, Λ/-2,7-dichloro-9-fluorenylmethylene, Λ/-ferrocenylmethyl, and Λ/-2-picolylamine N '-oxide. Imine Derivatives Imine derivatives include: Λ/-1 ,1-dimethylthiomethylene, Λ/-benzylidene, Λ/-p-methoxybenzylidene, Λ/-diphenylmethylene, Λ/-[(2-pyridyl)mesityl]methylene, N-(N ',N '-dimethylaminomethylene), N,N '-isopropylidene, Λ/-p-nitrobenzylidene, Λ/-salicylidene,
Λ/-5-chlorosalicylidene, Λ/-(5-chloro-2-hydroxyphenyl)phenyl-methylene, and Λ/-cyclohexylidene. Enamine Derivative An example of an enamine derivative is N- (5,5-dimethyl-3-oxo-1-cyclohexenyl). Λ/-Hetero Atom Derivatives Λ/-metal derivatives include: Λ/-borane derivatives, Λ/-diphenylborinic acid derivative, Λ/-[phenyl(pentacarbonylchromium- or -tungsten)]carbenyl, and Λ/-copper or Λ/-zinc chelate. Examples of Λ/-/V derivatives include: Λ/-nitro, Λ/-nitroso, and Λ/-oxide. Examples of Λ/-P derivatives include: Λ/-diphenylphosphinyl, Λ/-dimethylthiophosphinyl, Λ/-diphenylthiophosphinyl, Λ/-dialkyl phosphoryl, Λ/-dibenzyl phosphoryl, and Λ/-diphenyl phosphoryl. Examples of Λ/-sulfenyl derivatives include: Λ/-benzenesulfenyl, Λ/-o-nitrobenzenesulfenyl, Λ/-2,4-dinitrobenzenesulfenyl, Λ/-pentachlorobenzenesulfenyl, Λ/-2-nitro-4-methoxy-benzenesulfenyl, Λ/-t phenylmethylsulfenyl, and Λ/-3-nitropyridinesulfenyl. Λ/-sulfonyl derivatives include: Λ/-p-toluenesulfonyl, Λ/-benzenesulfonyl, Λ/-2,3,6-trimethyl- 4-methoxybenzenesulfonyl, Λ/-2,4,6-trimethoxybenzenesulfonyl, Λ/-2,6-dimethyl-4-methoxy- benzenesulfonyl, Λ/-pentamethylbenzenesulfonyl, Λ/-2,3,5,6-tetramethyl-4-methoxybenzene- sulfonyl, Λ/-4-methoxybenzenesulfonyl, Λ/-2,4,6-trimethylbenzenesulfonyl, Λ/-2,6-dimethoxy- 4-methylbenzenesulfonyl, Λ/-2,2,5,7,8-pentamethylchroman-6-sulfonyl, Λ/-methanesulfonyl, /V- ttrimethylsilylethanesuϊfonyl, Λ/-9-anthracenesulfonyl, Λ/-4-(4',8'-dimethoxynaphthylmethyl)-benzenesulfonyl, Λ/-benzylsulfonyl, /V-trifluoromethylsulfonyl, and Λ/-phenacylsulfonyl.
Disclosed compounds which are masked or protected may be prodrugs, compounds metabolized or otherwise transformed in vivo to yield a disclosed compound, e.g., transiently during metabolism. This transformation may be a hydrolysis or oxidation which results from contact with a bodily fluid such as blood, or the action of acids, or liver, gastrointestinal, or other enzymes.
Features of the invention are further described in the examples below. E. Examples
BIOLOGICAL EXAMPLES EXAMPLE 1
Effect of PD 198306 on streptozocin-induced static allodynia
Animals
Male Sprague Dawley rats (250-300g), obtained from Bantin and Kingman, (Hull, U.K.) were housed in groups of 3. All animals were kept under a 12h light/dark cycle (lights on at 07h OOmin) with food and water ad libitum. All experiments were carried out by an observer blind to drug treatments.
Development of diabetes in the rat
Diabetes was induced in rats by a single i.p. injection of streptozocin (50 mg/kg) as described previously (Courteix et al., 1993).
Evaluation of static allodynia
Mechanical hypersensitivity was measured using Semmes-Weinstein von Frey hairs (Stoelting, Illinois, U.S.A.). Animals were placed into wire mesh bottom cages allowing access to the underside of their paws. Animals were habituated to this environment prior to the start of the experiment. Mechanical hypersensitivity was tested by touching the plantar surface of the animals right hind paw with von Frey hairs in ascending order of force ( 0.7, 1.2, 1.5, 2, 3.6, 5.5, 8.5, 11.8, 15.1 and 29g) for up to 6 sec. Once a withdrawal response was established, the paw was re-tested, starting with the next descending von Frey hair until no response occurred. The highest force of 29 g lifted the paw as well as eliciting a response, thus represented the cut off point. The lowest amount of force required to elicit a response was recorded as the paw withdrawal threshold (PWT) in grams. Drugs
PD 198306 [N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide] and CI-1008 (pregabalin) were synthesized at Parke-Davis (Ann Arbor, Ml, USA). PD 198306 was suspended in cremophor:ethanol:water (1 :1 :8) vehicle. Pregabalin was dissolved in water. Both compounds were administered orally. Streptozocin (Aldrich, UK) was dissolved in 0.9% w/v NaCI and administered intraperitoneally. Drug administrations were made in a volume of 1 ml/kg.
Statistics
The static allodynia data were analysed using a Kruskall-Wallis ANOVA for non-parametric results, followed when significant by Mann-Whitney's t test.
Experimental protocol Static allodynia was assessed with von Frey hairs, before (baseline,
BL) and 1h after oral administration of PD 198306 (30mg/kg, p.o.), vehicle (cremophor:ethanol:water, 1 :1 :8) or pregabalin (30mg/kg, p.o.) (test). Animals were administered again the same compounds on the following day, both in the morning and the afternoon. Static allodynia was assessed only before and 1h after the afternoon administration, in order to minimise the habituation of the animals to the testing conditions. Animals treated with pregabalin received water in the morning administration, in order to avoid the potential development of tolerance to the compound with repeated administration.
Dav 1 : Day 2: a.m.: PD 198306 Water Vehicle
p.m.: BL p.m.: BL
PD 198306 PD 198306 Pregabalin Pregabalin
Vehicle Vehicle
Test Test
RESULTS
A single administration of pregabalin (30mg/kg, p.o.) significantly blocked streptozocin-induced static allodynia 1h after administration. In contrast, a single administration of PD 198306 (30mg/kg, p.o) had no effect on streptozocin-induced static allodynia 1 h after administration (see below). However, after the compound had been administered twice more on the following day, it significantly blocked streptozocin-induced static allodynia 1h after the third administration. The effects had disappeared by the following day (see FIG. 1).
EXAMPLE 2
MATERIALS AND METHODS Animals
Male Sprague Dawley rats (250-300g), obtained from Charles River, Margate, U.K.) were housed in groups of 3-6. All animals were kept under a 12h light/dark cycle (lights on at 07h OOmin) with food and water ad libitum. All experiments were carried out by an observer blind to drug treatments.
Diabetes was induced in rats by a single i.p. injection of streptozocin (50mg/kg) as described previously (Courteix et al., 1993).
Development of Chronic Constriction Injury in the rat
Animals were anaesthetised with 2% isoflurane 1 :4 O2/N20 mixture maintained during surgery via a nose cone. The sciatic nerve was ligated as previously described by Bennett and Xie, 1988. Animals were placed on a homeothermic blanket for the duration of the procedure. After surgical preparation the common sciatic nerve was exposed at the middle of the thigh by blunt dissection through biceps femoris. Proximal to the sciatic trifurcation, about 7mm of nerve was freed of adhering tissue and 4 ligatures (4-0 silk) were tied loosely around it with about 1mm spacing. The incision was closed in layers and the wound treated with topical antibiotics.
Intrathecal injections PD 198306 and pregabalin were administered intrathecally in a volume of 10 μl using a 100 μl Hamilton syringe by exposing the spine of the rats under brief isoflurane anaesthesia. Injections were made into the intrathecal space between lumbar region 5-6 with a 10 mm long 27 gauge needle. Penetrations were judged successful if there was a tail flick response. The wound was sealed with an autoclip and rats appeared fully awake within 2-3 min following injection.
Evaluation of static allodynia
Mechanical hypersensitivity was measured using Semmes-Weinstein von Frey hairs (Stoelting, Illinois, U.S.A.). Animals were placed into wire mesh bottom cages allowing access to the underside of their paws. Animals were habituated to this environment prior to the start of the experiment. Mechanical hypersensitivity was tested by touching the plantar surface of the animals right hind paw with von Frey hairs in ascending order of force ( 0.7, 1.2, 1.5, 2, 3.6, 5.5, 8.5, 11.8, 15.1 and 29g) for up to 6sec. Once a withdrawal response was established, the paw was re-tested, starting with the next descending von Frey hair until no response occurred. The highest force of 29g lifted the paw as well as eliciting a response, thus represented the cut off point. The lowest amount of force required to elicit a response was recorded as the paw withdrawal threshold (PWT) in grams.
Experimental protocol
Static allodynia was assessed with von Frey hairs, before (baseline, BL) and 0.5h, 1h and 2h after intrathecal or intraplantar administration of PD 198306 (1-30μg, i.t.), vehicle (cremophor:ethanol:water, 1 :1 :8) or pregabalin (10μg, i.t). For oral administration experiments, static allodynia was assessed with von Frey hairs, before (baseline, BL) and 1h after oral administration of PD 198306 (3-30mg/kg, p.o.), vehicle (cremophor:ethanol:water, 1 :1 :8) or pregabalin (30mg/kg, p.o.). Animals were administered again the same compounds on the following day, both in the morning and the afternoon. Static allodynia was assessed before and 1 h after the morning administration. In the afternoon static allodynia was assessed before, 1h, 2h and 3h after administration for streptozocin treated animals. CCI animals were assessed before, 1 h and 2h after administration
Drugs used
PD 198306 and pregabalin were synthesised at Parke-Davis (Ann Arbor, Ml, USA). PD 198306 was suspended in cremophor:ethanol:water (1 :1 :8) vehicle. Pregabalin was dissolved in water. Both compounds were administered orally, intrathecally or intraplantar in volumes of 1 ml/kg, 10μl and 100μl respectively. Streptozocin (Aldrich, UK) was dissolved in 0.9% w/v NaCI and administered intraperitoneally in a volume of 1 ml/kg.
Statistics
Data were analysed using a Kruskall-Wallis ANOVA for non-parametric results, followed when significant by Mann-Whitney's t test vs vehicle group.
RESULTS 1. Effects of PD 198306 on static allodynia, following systemic administration
1.1. Effect of PD198306 on streptozocin-induced static allodynia A single administration of pregabalin (30mg/kg, p.o.) significantly blocked streptozocin-induced static allodynia 1h after administration. In contrast, a single administration of PD 198306 (3-30mg/kg, p.o) had no effect on streptozocin-induced static allodynia 1 h after administration (FIG. 2). However, after the compound had been administered twice more on the following day, PD 198306 (30mg/kg) significantly blocked streptozocin- induced static allodynia for 2h after the third administration (FIG. 2).
1.2. Effect of PD198306 on CCI-induced static allodynia A single administration of pregabalin (30mg/kg, p.o.) significantly blocked CCI- induced static allodynia 1 h after administration. In contrast, neither a single or multiple administration of PD 198306 (3-30mg/kg, p.o) had any effect on CCI- induced static allodynia (FIG. 3).
2. Effects of PD 198306 on static allodynia, following intrathecal administration
Intrathecally administered PD198306 (1-30μg) dose-dependently blocked the maintenance of static allodynia in both streptozocin (FIG. 4) and CCI animals (FIG. 5) with respective MEDs of 3 and 10 μg. This antiallodynic effect lasted foM h.
3. Effects of PD 198306 on static allodynia, following intraplantar administration
An intrathecal administration of PD 198306 (30μg) significantly blocked static allodynia in both neuropathic pain models (FIGS. 6,7). In contrast, a single administration of PD 198306 at a dose 100-fold higher (3mg/100μl) directly into the paw had no effect on streptozocin (FIG. 6) or CCI-induced static allodynia (FIG. 7).
REFERENCES Bennett GJ, Xie Y-K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988;33:87-107.
Courteix C, Eschalier A and Lavarenne J. Streptozocin -induced rats: behavioural evidence for a model of chronic pain. Pain 1993;53:81-8
EXAMPLE 3 Effect of other MEK inhibitors in a neuropathic pain model in the rat
SUMMARY The effect of several MEK inhibitors, with different binding affinities, has been investigated in the CCI model of neuropathic pain in the rat, by assessing static allodynia with von Frey hairs. Intrathecal administration of PD219622 or PD297447 (30μg) had no significant effect on allodynia. This lack of effect may reflect the low affinity or solubility of the compounds. However, intrathecal administration of PD 254552 or PD 184352 (30μg), which posses higher binding affinities, blocked the maintenance of static allodynia in CCI animals. The antiallodynic effect was only evident for 30min post-injection and thus, shorter than the one observed for pregabalin (100μg). The magnitude of the effect was similar for 30μg of PD 184352 and 100μg of pregabalin. From this study it is concluded that MEK inhibitors exert an antiallodynic effect in CCI-induced neuropathic rats when administered intrathecally, and that the antiallodynic effect correlates with the affinity of the compounds.
The animals and methods for developing chronic constriction injury in the rat, injecting test compounds, and evaluation of static allodynia were according to Example 2 above. PD219622, PD297447, PD 184352, PD 254552 and pregabalin were administered intrathecally at doses of 30 g for all PD compounds and 100μg for pregabalin. Static allodynia was assessed with von Frey hairs, before (baseline, BL) and 0.5h, 1 h and 2h after intrathecal administration of the compounds
Drugs used PD297447, PD219622, PD 254552, PD 184352 (CI-1040), and pregabalin were synthesised at Parke-Davis (Ann Arbor, Ml, USA). PD297447, PD219622, PD 254552 and PD 184352 were suspended in cremophor:ethanol:water (1 :1 :8) vehicle. Pregabalin was dissolved in water. All compounds were administered intrathecally in a 10μl volume.
Statistics
Data were analysed using a Kruskall-Wallis ANOVA for non-parametric results, followed when significant by Mann-Whitney's t test vs vehicle group.
RESULTS
Intrathecally administered PD297447 or PD219622 (30μg) had no significant effect on allodynia. This lack of effect may reflect the low affinity of the compounds (965nM and 100nM respectively). However, intrathecal administration of PD 184352 or PD 254552 (30μg) blocked the maintenance of static allodynia in CCI animals (see FIG. 8). These compounds possess higher affinity (2 and 5 nM respectively). The antiallodynic effect was only evident for 30min post-injection and thus, shorter than the one observed for pregabalin (100μg). The magnitude of the effect was similar for 30μg of PD 184352 and 100μg of pregabalin.
The results indicate that MEK inhibitors exert an antiallodynic effect in CCI-induced neuropathic rats when administered intrathecally, and that the antiallodynic effect correlates with the affinity of the compounds.
CHEMICAL EXAMPLES EXAMPLE 1 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide (a) Preparation of 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
To a stirred solution containing 3.16 g (0.0133 mol) of 2-amino- 5-iodotoluene in 5 mL of tetrahydrofuran at -78°C was added 10 mL (0.020 mol) of a 2.0 M lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (Aldrich) solution. The resulting green suspension was stirred vigorously for 15 minutes, after which time a solution of 1.00 g (0.00632 mol) of 2,4-difluorobenzoic acid in 10 mL of tetrahydrofuran was added. The reaction temperature was allowed to increase slowly to room temperature, at which temperature the mixture was stirred for 2 days. The reaction mixture was concentrated by evaporation of the solvent under reduced pressure. Aqueous HCI (10%) was added to the concentrate, and the solution was extracted with dichloromethane. The organic phase was dried (MgS04) 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;
1 H NMR (400 MHz, DMSO): δ 9.72 (s, 1 H), 7.97 (dd, 1 H, J=7.0, 8.7 Hz), 7.70 (d, 1 H, J=1.5 Hz), 7.57 (dd, 1 H, J=8.4, 1.9 Hz), 7.17 (d, 1 H, J=8.2 Hz), 6.61-6.53 (m, 2H), 2.18 (s, 3H);
1 c NMR (100 MHz, DMSO): δ 169.87, 166.36 (d, Jc-F=249.4 Hz), 150.11 (d, -4 Hz), 139.83, 138.49, 136.07, 135.26 (d, -5 Hz), 135.07, 125.60, 109.32, 104.98 (d, 1 Hz), 99.54 (d, Jc-F=26.0 Hz), 89.43, 17.52; 19F NMR (376 MHz, DMSO): δ -104.00 to -104.07 (m);
IR (KBr) 1670 (C=O stretch)cm"1 ; MS (Cl) M+1 = 372. Analysis calculated for C14H11 FINO2:
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-hydroxy-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
([benzotriazolyloxy]tripyrrolidino 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 dichloromethane → dichloromethane-methanol (166:1) 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; 1 H NMR (400 MHz, DMSO): δ 11.34 (s, 1 H), 9.68 (s, 1 H), 9.18 (s, 1 H), 7.65 (d, 1 H, J=1.5 Hz), 7.58 (dd, 1 H, J=8.7, 6.8 Hz), 7.52 (dd, 1 H, J=8.4, 1.9 Hz), 7.15 (d, 1 H, J=8.4 Hz), 6.74 (dd, 1 H, J=11.8, 2.4 Hz), 6.62 (ddd, 1 H, 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, -5 Hz), 122.23, 112.52,
104.72 (d, J=22.1 Hz), 100.45 (d, Jc-F=25.2 Hz), 86.77, 17.03; 19F NMR (376 MHz, DMSO): δ -107.20 to -107.27 (m); IR (KBr) 3307 (broad, O-H stretch), 1636 (C=O stretch) cm"1 ; MS (Cl) M+1 = 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 2 5-Bromo-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide (a) Preparation of 5-Bromo-2,3,4-trifluorobenzoic acid
To a stirred solution comprised of 1-bromo-2,3,4-thfluorobenzene (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. HCI (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; 1 H NMR (400 MHz, DMSO): δ 13.97 (broad s, 1 H, 8.00-7.96 (m, 1 H); 1 c 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)crτr1 ; MS (Cl) M+1 = 255. Analysis calculated for C74H2i BrF3θ2:
C, 32.97; H, 0.79; N, 0.00; Br, 31.34; F, 22.35. Found: C, 33.18; H, 0.64; N, 0.01 ; Br, 30.14; F, 22.75.
(b) Preparation of 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzoic acid
To a stirred solution comprised of 1.88 g (0.00791 mol) of 2-amino- 5-iodotoluene in 10 mL of tetrahydrofuran at -78°C was added 6 mL (0.012 mol) of a 2.0 M lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (Aldrich) solution. The resulting green suspension was stirred vigorously for 10 minutes, after which time a solution of 1.00 g (0.00392 mol) of 5-bromo-2,3,4-trifluorobenzoic acid in 15 mL of tetrahydrofuran was added. The cold bath was subsequently removed, and the reaction mixture stirred for 18 hours. The mixture was concentrated, and the concentrate was treated with 100 mL of dilute (10%) aqueous hydrochloric acid. The resulting suspension was extracted with ether (2 x 150 mL), and the combined organic extractions were dried (MgSO4) and concentrated in vacuo to give an orange solid. The solid was triturated with boiling dichloromethane, cooled to ambient temperature, and collected by filtration. The solid was rinsed with dichloromethane, and dried in the vacuum-oven (80°C) to afford 1.39 g (76%) of a yellow-green powder; mp 259.5-262°C;
1 H NMR (400 MHz, DMSO): δ 9.03 (s, 1 H), 7.99 (dd, 1 H, J=7.5, 1.9 Hz), 7.57 (dd, 1 H, J=1.5 Hz), 7.42 (dd, 1 H, J=8.4, 1.9 Hz), 6.70 (dd, 1 H, 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)cm-1 ;
MS (Cl) M+1 = 469.
Analysis calculated for Ci4HgBrF2lNO2:
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-hydroxy-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 (g9:1) 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;
1 H NMR (400 MHz, DMSO): δ 11.53 (s, 1 H), 9.38 (s, 1 H), 8.82 (s, 1 H), 7.70 (dd, 1 H, J=7.0, 1.9 Hz), 7.53 (s, 1 H), 7.37 (dd, 1 H, J=8.4, 1.9 Hz), 6.55 (dd, 1 H, 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-1 ; MS (Cl) M+1 = 484. Analysis calculated for Ci4H nBrF2lN2θ2:
C, 34.81 ; H, 2.09; N, 5.80. Found: C, 34.53; H, 1.73; N, 5.52,
Examples 3 to 12 and 78 to 102 in the table below were prepared by the general procedures of Examples 1 and 2.
EXAMPLES 13-77
Examples 13 to 77 were prepared utilizing combinatorial synthetic methodology by reacting appropriately substituted phenylamino benzoic acids
Re
I (e.g., as shown in Scheme 1) and hydroxylamines (e.g., HN-O-R7). 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 derivatised 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 3-102 Example Compound Melting MS
No. Point (°C) (M-H+)
3 2-(4-bromo-2-methyl-phenylamino)-4-fluoro- 56-75 dec 523 N-hydroxy-benzamide
4 5-Chloro-N-hydroxy-2-(4-iodo-2-methyl- 65 dec phenylamino)-benzamide
5 5-Chloro-N-hydroxy-2-(4-iodo-2-methyl- 62-67 phenylamino)-N-methyl-benzamide
6 5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 105-108 N-(terahydropyran-2-yloxy)benzamide
7 5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 64-68 N-methoxybenzamide
8 4-Fluoro-N-hydroxy-2-(4-fluoro-2-methyl- 119-135 phenylamino)-benzamide
9 4-Fluoro-N-hydroxy-2-(2-methyl 101-103 phenylamino)-benzamide
10 4-Fluoro-2-(4-fluor-2-methyl-phenylamino)- 142-146 N-(terahydropyran-2-yloxy)benzamide Example Compound Melting MS
No. Point (°C) (M-H+) ϊϊ 4-Fluoro-N-hydroxy-2-(4-cluoro-2-methyl- 133.5-135 phenylamino)-benzamide
12 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 107-109.5 N-phenylmethoxy-benzamide
13 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 399 N-methoxy-benzamide
14 3,4-Difluoro-2-(4-iodo-2-methyl- 417 phenylamino)-N-methoxy-benzamide
15 2-(4-Bromo-2-methyl-phenylamino)- 369 3,4-difluoro-N-methoxy-benzamide
16 2-(4-Bromo-2-methyl-phenylamino)-N- 342* ethoxy-3,4-difluoro-benzamide (M-EtO)
17 5-Bromo-N-ethoxy-3,4-difluoro-2-(4-iodo- 509 2-methyl-phenylamino)-benzamide
18 3,4-Difluoro-2-(4-iodo-2-methyl- 445 phenylamino)-N-isopropoxy-benzamide
19 2-(4-Bromo-2-methyl-phenylamino)- 397 3,4-difluoro-N-isopropoxy-benzamide
20 4-Fluoro-N-(furan-3-ylmethoxy)-2-(4-iodo- 465 2-methyl-phenylamino)-benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
21 3,4-Difluoro-N-(furan-3-ylmethoxy)- 483 2-(4-iodo-2-methyl-phenylamino)-benzamide
22 2-(4-Bromo-2-methyl-phenylamino)- 435 3,4-difluoro-N-(furan-3-ylmethoxy)- benzamide
23 5-Bromo-3,4-difluoro-N-(furan-3-ylmethoxy)- 561 2-(4-iodo-2-methyl-phenylamino)-benzamide
24 5-Bromo-N-(but-2-enyloxy)-3,4-difluoro- 536 2-(4-iodo-2-methyl-phenylamino)-benzamide
25 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 423 N-(prop-2-ynyloxy)-benzamide
26 3,4-Difluoro-2-(4-iodo-2-methyl- 441 phenylamino)-N-(prop-2-ynyloxy)- benzamide
27 3,4-Difluoro-2-(4-iodo-2-methyl- 455 phenylamino)-N-(1-methyl-prop-2-ynyloxy)- benzamide
28 2-(4-Bromo-2-methyl-phenylamino)- 407 3,4-difluoro-N-(1-methyl-prop-2-ynyloxy)- benzamide
29 N-(But-3-ynyloxy)-3,4-difluoro-2-(4-iodo- 455 2-methyl-phenylamino)-benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
30 2-(4-Bromo-2-methyl-phenylamino)-N-(but- 407 3-ynyloxy)-3,4-difluoro-benzamide
31 5-Bromo-N-(but-3-ynyloxy)-3,4-difluoro- 533 2-(4-iodo-2-methyl-phenylamino)-benzamide
32 3,4-Difluoro-2-(4-iodo-2-methyl- 517 phenylamino)-N-(3-phenyl-prop-2-ynyloxy)- benzamide
33 3,4-Difluoro-2-(4-bromo-2-methyl- 469 phenylamino)-N-(3-phenyl-prop-2-ynyloxy)- benzamide
34 3,4-Difluoro-N-[3-(3-fluoro-phenyl)-prop- 535 2-ynyloxy]-2-(4-iodo-2-methyl-phenylamino)- benzamide
35 2-(4-Bromo-2-methyl-phenylamino)- 487 3,4-difluoro-N-[3-(3-fluoro-phenyl)-prop- 2-ynyloxy]-benzamide
36 3,4-Difluoro-N-[3-(2-fluoro-phenyl)-prop- 535 2-ynyloxy]-2-(4-iodo-2-methyl-phenylamino)- benzamide
37 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+)
39 2-(4-Bromo-2-methyl-phenylamino)- 510 3,4-difluoro-N-(3-methyl-5-phenyl-pent-2-en- 4-ynyloxy)-benzamide
40 N-Ethoxy-3,4-difluoro-2-(4-iodo-2-methyl- 431 phenylamino)-benzamide
41 2-(4-Bromo-2-methyl-phenylamino)-N- 383 ethoxy-3,4-difluoro-benzamide
42 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 427 N-propoxy-benzamide
43 3,4-Difluoro-2-(4-iodo-2-methyl- 445 phenylamino)-N-propoxy-benzamide
44 2-(4-Bromo-2-methyl-phenylamino)- 397 3,4-difluoro-N-propoxy-benzamide
45 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 523 phenylamino)-N-propoxy-benzamide
46 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 427 N-isopropoxy-benzamide
47 3,4-Difluoro-2-(4-iodo-2-methyl- 445 phenylamino)-N-isopropoxy-benzamide
48 2-(4-Bromo-2-methyl-phenylamino)- 397 3,4-difluoro-N-isopropoxy-benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
4 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 523 phenylamino)-N-isopropoxy-benzamide
50 N-Cyclobutyloxy-3,4-difluoro-2-(4-iodo- 457 2-methyl-phenylamino)-benzamide
51 2-(4-Bromo-2-methyl-phenylamino)-N- 409 cyclobutyloxy-3,4-difluoro-benzamide
52 N-Cyclopentyloxy-4-fluoro-2-(4-iodo- 453 2-methyl-phenylamino)-benzamide
53 N-Cyclopentyloxy-3,4-difluoro-2-(4-iodo- 471 2-methyl-phenylamino)-benzamide
54 2-(4-Bromo-2-methyl-phenylamino)-N- 423 cyclopentyloxy-3,4-difluoro-benzamide
55 N-Cyclopropylmethoxy-4-fluoro-2-(4-iodo- 439 2-methyl-phenylamino)-benzamide
56 N-Cyclopropylmethoxy-3,4-difluoro- 457 2-(4-iodo-2-methyl-phenylamino)-benzamide
57 2-(4-Bromo-2-methyl-phenylamino)-N- 409 cyclopropylmethoxy-3,4-difluoro-benzamide
58 5-Bromo-N-cyclopropylmethoxy-3,4-difluoro- 435 2-(4-iodo-2-methyl-phenylamino) Example Compound Melting MS No. Point (°C) (M-H+)
59 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 505 N-(2-phenoxy-ethoxy)-benzamide
60 3,4-Difluoro-2-(4-iodo-2-methyl- 523 phenylamino)-N-(2-phenoxy-ethoxy)- benzamide
61 2-(4-Bromo-2-methyl-phenylamino)- 475 3,4-difluoro-N-(2-phenoxy-ethoxy)- benzamide
62 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 481 N-(thiophen-2-ylmethoxy)-benzamide
63 3,4-Difluoro-2-(4-iodo-2-methyl- 499 phenylamino)-N-(thiophen-2-ylmethoxy)- benzamide
64 2-(4-Bromo-2-methyl-phenylamino)- 451 3,4-difluoro-N-(thiophen-2-ylmethoxy)- benzamide
65 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 439 N-(2-methyl-allyloxy)-benzamide
66 3,4-Difluoro-2-(4-iodo-2-methyl- 457 phenylamino)-N-(2-methyl-allyloxy)- benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
67 2-(4-Bromo-2-methyl-phenylamino)- 410 3,4-difluoro-N-(2-methyl-allyloxy)-benzamide
68 N-(But-2-enyloxy)-4-fluoro-2-(4-iodo- 439 2-methyl-phenylamino)-benzamide
69 N-(But-2-enyloxy)-3,4-difluoro-2-(4-iodo- 457 2-methyl-phenylamino)-benzamide
70 2-(4-Bromo-2-methyl-phenylamino)-N-(but- 410 2-enyloxy)-3,4-difluoro-benzamide
71 3,4-Difluoro-2-(4-iodo-2-methyl- 441 phenylamino)-N-(prop-2-ynyloxy)- benzamide
72 N-(But-3-ynyloxy)-3,4-difluoro-2-(4-iodo- 455 2-methyl-phenylamino)-benzamide
73 2-(4-Bromo-2-methyl-phenylamino)-N- 449 (4,4-dimethyl-pent-2-ynyloxy)-3,4-difluoro- benzamide
74 N-(But-2-enyloxy)-3,4-difluoro-2-(4-iodo- 457 2-methyl-phenylamino)-benzamide
75 2-(4-Bromo-2-methyl-phenylamino)-N-(but- 410 2-enyloxy)-3,4-difluoro-benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
76 N-(3-tert.-butyl-propyn-2-yl)oxy-4-fluoro- 479 2-(4-iodo-2-methyl-phenylamino)-benzamide
77 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 577 * N-phenylmethoxy-benzamide *CI
78 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl- oil phenylamino)-N-isopropyl-benzamide
79 N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4- 125-127 iodo-2-methyl-phenylamino)-benzamide
80 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl- 45-55 phenylamino)-N-methyl-benzamide
81 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl- 208-209 phenylamino)-5-nitro-benzamide (GLASS)
82 2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy- 199-200 4-nitro-benzamide
83 3,4-Difluoro-2-(4-iodo-2-methyl- 163-165 phenylamino)-N-(tetrahydro-pyran-2-yloxy)- benzamide
84 3,4-Difluoro-N-hydroxy-2-(4-iodo-2-methyl- 65-75 phenylamino)-benzamide Example Compound Melting MS
No. ' Point (°C) (M-H+)
85 3,4-Difluoro-5-bromo-2-(4-iodo-2-methyl- 95 phenylamino)-N-(2-piperidin-1-yl-ethoxy)- benzamide
86 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 167-169 phenylamino)-N-(tetrahydro-pyran-2-yloxy)- benzamide
87 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N- 165-169 hydroxy-benzamide (HCI salt)
88 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N- 166-167.5 (tetrahydro-pyran-2-yloxy)-benzamide
89 3,4-Difluoro-2-(2-chloro-4-iodo- 173-174 phenylamino)-N-cyclobutylmethoxy- benzamide
90 3,4-Difluoro-2-(2-chloro-4-iodo- 121-122 phenylamino)-N-(tetrahydro-pyran-2-yloxy)- benzamide
91 5-Bromo-2-(2-chloro-4-iodo-phenylamino)- 206-211.5 N-(2-dimethylamino-ethoxy)-3,4-difluoro- DEC benzamide monohydrochloride salt
92 5-Bromo-N-(2-dimethylamino-propoxy)-3,4- 95-105 difluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
93 5-Bromo-2-(2-chloro-4-iodo-phenylamino)- 266-280 3,4-difluoro-N-hydroxy-benzamide DEC
94 5-Bromo-2-(2-chloro-4-iodo-phenylamino)- 167.5-169.5 3,4-difluoro-N-(tetrahydro-pyran-2-yloxy)- benzamide
95 3,4-Difluoro-2-(2-chloro-4-iodo- 172.5-173.5 phenylamino)-N-cyclopropylmethoxy- benzamide
96 5-Bromo-2-(2-chloro-4-iodo-phenylamino)- 171-172.5 N-cyclopropylmethoxy-3,4-difluoro- benzamide
97 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 173.5-175 phenylamino)-N-(2-morpholin-4-yl-ethoxy)- benzamide
98 5-Bromo-N-(2-diethylamino-ethoxy)-3,4- 81 DEC difluoro-(4-iodo-2-methyl-phenylamino)- benzamide
99 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 126-128 phenylamino)-N-isobutoxy-benzamide
100 5-Bromo-N-cyclohexylmethoxy-3,4-difluoro- 139-142 2-(4-iodo-2-methyl-phenylamino)-benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
101 5-Bromo-N-cyclopentylmethoxy-3,4-difluoro- 113-115 2-(4-iodo-2-methyl-phenylamino)-benzamide
102 5-Bromo-N-cyclobutylmethoxy-3,4-difluoro- 138-139 2-(4-iodo-2-methyl-phenylamino)-benzamide
The invention compounds are useful in treating chronic pain proliferative diseases by virtue of their selective inhibition of the dual specificity protein kinases MEKi and MEK2. The invention compound has been evaluated in a number of biological assays which are normally utilized to establish inhibition of proteins and kinases, and to measure mitogenic and metabolic responses to such inhibition.
EXAMPLE 1A 4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid
To a stirring solution comprised of 3.16 g (0.0133 mol) of 2-amino- 5-iodotoluene in 5 mL of tetrahydrofuran at -78°C was added 10 mL (0.020 mol) of a 2.0 M lithium diisopropylamide in tetrahydrofuran/heptane/ethenylbenzene (Aldrich) solution. The resulting green suspension was stirred vigorously for 15 minutes, after which time a solution of 1.00 g (0.00632 mol) of 2,4-difluorobenzoic acid in 10 mL of tetrahydrofuran was added. The reaction temperature was allowed to increase slowly to room temperature, at which temperature it was stirred for 2 days. The reaction mixture was concentrated. Aqueous HCI (10%) was added to the concentrate, and the solution was extracted with dichloromethane. The organic phase was dried (MgSO4) and then boiled over a steambath to low volume and cooled to room temperature. The off-white fibers were collected by vacuum filtration, rinsed with hexanes, and vacuum-oven dried. (76°C; ca. 10 mm of Hg) to afford 1.10 g (47%) of the desired material; mp 224-229.5°C; H NMR (400 MHz; DMSO): δ 9.72 (s, 1 H), 7.97 (dd, 1 H, J = 7.0, 8.7 Hz), 7.70 (d, 1 H, J = 1.5 Hz), 7.57 (dd, 1 H, J = 8.4, 1.9 Hz), 7.17 (d, 1 H, J = 8.2 Hz), 6.61-6.53 (m, 2H), 2.18 (s, 3H); 3C 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 (Cl) M+1 = 372. Analysis calculated for C14H11 FINO2: C, 45.31 ; H, 2.99; N, 3.77. Found: C, 45.21 ; H, 2.77; N, 3.64.
EXAMPLES 2A-30A By following the general procedure of Example 1A, the following benzoic acids and salts were prepared:
Example Compound MP °C
No.
2A 3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)- 206-210 benzoic acid
3A 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 240.5-244.5 benzoic acid
4A 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 259.5-262 phenylamino)-benzoic acid
5A 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-benzoic 255-260 acid
6A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic 234-238 acid Example Compound MP °C
No.
7A Sodium 5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 310-320 DE benzoate C
8A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic 239.5-240 acid
9A 2-(2-Chloro-4-iodo-phenylamino)-5-nitro-benzoic 289-293 acid
10A 4-Fluoro-2-(3-fluoro-4-iodo-2-methyl-phenylamino)- 233-235 benzoic acid
11A 2-(4-lodo-2-methyl-phenylamino)-5-nitro-benzoic 264-267 acid
12A 2-(2-Fluoro-4-iodo-phenylamino)-5-nitro-benzoic 256-258 acid
13A 2-(4-Bromo-2-methyl-phenylamino)-4-fluoro- 218.5-220 benzoic acid
14A 2-(2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic 285-288 DE acid C
15A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro- 230-234 benzoic acid
16A 3-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic 218-221 acid
17A 3,4-Difluoro-2-(4-iodo-2-methoxy-phenylamino)- 230-233 benzoic acid Example Compound MP °C
No.
18A 4-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic 245-255 DE acid C
19A 2-(4-lodo-2-methyl-phenylamino)-benzoic acid 218-223
20A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic 243-46 acid
21A 5-lodo-2-(4-iodo-2-methyl-phenylamino)-benzoic 241-245 acid
26A 2-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzoic 179-182 acid
27A 4-Fluoro2-(2,3-dimethyl-4-iodo-2-methyl- 258-261 phenylamino)-benzoic acid
28A 5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic 209.5-211 acid
29A 2-Chloro-6-(4-iodo-2-methyl-phenylamino)-benzoic 171-175 acid
30A 2-(4-lodo-2-methyl-phenylamino)-4-nitro-benzoic 251-263 acid
EXAMPLE 31A 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; H NMR (400 MHz; CDCI3): δ 9.11 (s, 1 H), 7.56 (d, 1H, J = 1.4 Hz), 7.46-7.41 (m, 2H), 7.20 (dd, 1 H, J = 8.9, 2.4 Hz), 7.00 (t, 2H, J = 9.6 Hz), 6.55 (broad t, 1 H), 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, 1 H);
IR (KBr) 3297 (O-H stretch), 1627 (C = O stretch) cm-1 ; MS (Cl) M+1 = 431. Analysis calculated for C16H16CIIN2O2:
C, 44.62; H, 3.74; N, 6.50. Found: C, 44.63; H, 3.67; N, 6.30.
EXAMPLES 32-48A By following the general procedure of Example 31A, the following benzamides were prepared by reacting the corresponding benzoic acid with the corresponding amine.
Example Compound MP °C
No. 32A 4-Methoxy-N-(4-methoxy-phenyl)-3-nitro- 153.5-156 benzamide 33A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 158 benzamide 34A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 102.5-104.5 methyl-benzamide 35A N-Ethyl-4-fluoro-2-(4-iodo-2-methyl- 90-91 phenylamino)-benzamide 36A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N- oil dimethyl-benzamide 37A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 285-288 DE
(1 H-tetrazol-5-yl)-benzamide C
38A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)- 180-182 benzamide 39A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N- 137-138 dimethyl-benzamide 40A [5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 170-173 benzoylaminoj-acetic acid 41 A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 69-71 propyl-benzamide 42A 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo- 132-133.4
2-methyl-phenylamino)-benzamide 43A N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl- oil phenylamino)-benzamide 44A 4-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin- 122-124
1-yl]-propyl}-2-(4-iodo-2-methyl-phenylamino)- benzamide 45A N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)- 91-93
5-nitro-benzamide 46A N-Butyl-4-fluoro-2-(4-iodo-2-methyl- 97-99 phenylamino)-benzamide Example Compound MP °C
No. 47A 5-Chloro-N,N-diethyl-2-(4-iodo-2-methyl- 118-120 phenylamino)-benzamide 48A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N,N- 142.5-144 dimethyl-benzamide
EXAMPLE 49A
A4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohoW-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; 1 H NMR (400 MHz; DMSO): δ 7.57 (d, 1 H, J=1.7 Hz), 7.45 (dd, 1 H, J=8.4, 1.9 Hz), 7.39 (s, 1 H), 7.29 (t, 1 H, J=7.5 Hz), 6.89 (d, 1 H, J=8.4 Hz), 6.67-6.60 (m, 1 H), 5.47 (t, 1 H, J=5.5 Hz), 4.49 (d, 2H, 5.1 Hz), 2.14 (s, 3H);
IR (KBr) 3372 (O-H stretch) crrr1; MS (Cl) M+1 = 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 50A-52A
The following benzyl alcohols were prepared by the general procedure of Example 49A. Example Compound MP °C No.
50A [5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 82-85 phenylj- ethanol
51 A [2-(4-lodo-2-methyl-phenylamino)-5-nitro- 126.5-128. phenyl]-methanol 5
52A [5-Bromo-2-(4-iodo-2-methyl-phenylamino)- 60.5-63.5 phenyl]-methanol
Several invention compounds of Formula l(A) 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 (2M solution in Hunig's base and 1 M in amine in DMF). A 0.5M 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 53A-206A The following compounds of Formula I were prepared by combinatorial methodology:
Example Compound MS
No. M-H
53A 5-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo- 510
2-methyl-phenylamino)-benzamide 54A N-(2,3-Dihydroxy-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- 462 phenylamino)-benzamide 55A 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 577
(2-piperidin-1-yl-ethyl)-benzamide 56A 3,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 432 phenylamino)-benzamide 57A N-(2,3-Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl- 444 phenylamino)-benzamide 58A 3,4-Difluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 446 phenylamino)-benzamide 59A 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 564
(2-pyrrolidin-1-yl-ethyl)-benzamide 60A 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 571
(2-pyridin-4-yl-ethyl)-benzamide 61 A 4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 414 phenylamino)-benzamide 62A 5-Bromo-N-(3-dimethylamino-propyl)-3,4-difluoro-2-(4-iodo- 551
2-methyl-phenylamino)-benzamide 63A 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 580
(2-morpholin-4-yl-ethyl)-benzamide 64A 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 501
(2-morpholin-4-yl-ethyl)-benzamide 65A 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 485
(2-pyrrolidin-1-yl-ethyl)-benzamide Example Compound MS
No. M-H
66A 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin- 493
4-yl-ethyl)-benzamide 67A N-(3-Dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- 473 phenylamino)-benzamide 68A N-Benzyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)- 460 benzamide 69A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 384
(2-hydroxy-ethyl)-benzamide 70A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin- 483
4-yl-ethyl)-benzamide 71 A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 495
1 -yl-propyl)-benzamide 72A 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 513
1 -yl-propyl)-benzamide 73A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thiophen- 480
2-yl-ethyl)-benzamide 74A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 467
1 -yl-ethyl)-benzamide 75A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 453
(2-morpholin-4-yl-ethyl)-benzamide 76A 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 557 pyridin-4-ylmethyl-benzamide 77A 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyhdin- 479
4-ylmethyl-benzamide 78A 2-(4-Bromo-2-methyl-phenylamino)-N-(3-dimethylamino- 425 propyl)-3,4-difluoro-benzamide 79A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin- 461
4-ylmethyl-benzamide 80A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- 475 ethyl)-benzamide 81 A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyridin- 445
4-yl-ethyl)-benzamide 82A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 400
(3-hydroxy-propyl)-benzamide Example Compound MS
No. M-H
83A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 437
(2-pyrrolidin-1-yl-ethyl)-benzamide 84A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyl- 474 benzamide 85A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 450
(2-thiophen-2-yl-ethyl)-benzamide 86A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-pyridin- 431
4-ylmethyl-benzamide 87A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 444 phenethyl-benzamide 88A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 451
(2-piperidin-1-yl-ethyl)-benzamide 89A 5-Chloro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1 -yl]-propyl}- 557*
2-(4-iodo-2-methyl-phenylamino)-benzamide 90A 5-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}- 541*
2-(4-iodo-2-methyl-phenylamino)-benzamide 91A 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl 487 methyl-benzamide 92A 5-Bromo-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}- 601*
2-(4-iodo-2-methyl- phenylamino)-benzamide 93A 5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- 486* phenylamino)-benzamide 94A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- 497*
1 -yl-ethyl)-benzamide 95A (3-Hydroxy-pyrrolidin-1-yl)-[2-(4-iodo-2-methyl- 466 phenylamino)-5-nitro-phenyl]- 96A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 484*
1 -yl-ethyl)-benzamide 97A 5-Bromo-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- 530* phenylamino)-benzamide 98A N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-chloro-2-(4-iodo- 518*
2-methyl- phenylamino)-benzamide Example Compound MS
No. M-H
99A N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-bromo-2-(4-iodo- 562*
2-methyl- phenylamino)-benzamide 100A [5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl]- 499
(3-hydroxy-pyrrolidin-1 -yl)- 101A 2-(4-lodo-2-methyl-phenylamino)-5-nitro-benzoic acid 501 phenethyl ester 102A N-{3-[4-(2-Hydroxy-ethyl)-piperazin-1 -yl]-propyl}-2-(4-iodo- 568*
2-methyl-phenylamino)-benzamide 103A [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- 455
(3-hydroxy-pyrrolidin-1 -yl)- 104A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin- 460
4-ylmethyl-benzamide 105A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 528*
1 -yl-ethyl)-benzamide 106A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- 542*
1 -yl-ethyl)-benzamide 107A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 468*
1 -yl-ethyl)-benzamide 108A 5-Chloro-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- 472* phenylamino)-benzamide 109A N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-fluoro-2-(4-iodo- 502*
2-methyl-phenylamino)-benzamide 110A 5-Chloro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 445* phenylamino)-benzamide 111A 5-Chloro-N-(3-diethylamino-2-hydroxy-propyl)-2-(4-iodo- 516*
2-methyl-phenylamino)-benzamide 112A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- 482*
1 -yl-ethyl)-benzamide 113A 5-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 489* phenylamino)-benzamide 114A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 556*
1 -yl-propyl)-benzamide Example Compound MS
No. M-H
115A N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-2-(4-iodo-2-methyl- 529* phenylamino)-5-nitro-benzamide 116A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin- 500*
4-yl-ethyl)-benzamide 117A 5-Chloro-N-(3-diethylamino-propyl)-2-(4-iodo-2-methyl- 500* phenylamino)-benzamide 118A 5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- 514* phenylamino)-benzamide 119A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 512*
1 -yl-propyl)-benzamide 120A 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin-1 -yl- 509* ethyl)-benzamide 121 A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin- 544*
1 -yl-ethyl)-benzamide 122A N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl- 470* phenylamino)-benzamide 123A 5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- 516* phenylamino)-benzamide 124A N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- 456*
5-nitro-benzamide 125A 5-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 429* phenylamino)-benzamide 126A N-(3-Diethylamino-propyl)-5-fluoro-2-(4-iodo-2-methyl- 484* phenylamino)-benzamide 127A N-(3-Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- 511*
5-nitro-benzamide 128A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin- 544*
4-yl-ethyl)-benzamide 129A 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin-1 -yl- 523* propyl)-benzamide 130A [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- 439
(3-hydroxy-pyrrolidin-1 -yl)- Example Compound MS
No. M-H
131A 5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- 558* phenylamino)-benzamide 132A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin- 484*
4-yl-ethyl)-benzamide 133A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 496*
1 -yl-propyl)-benzamide 134A [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- 482
[4-(2-hydroxy-ethyl)-piperazin-1- 135A N-(3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo- 500*
2-methyl-phenylamino)-benzamide 136A [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoylamino]- 443 acetic acid 137A 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(2-pyrrolidin-1 -yl- 495* ethyl)-benzamide 138A N-(3-Dimethylamino-propyl)-2-(4-iodo-2-methyl- 483* phenylamino)-5-nitro-benzamide 139A N-(2-Diisopropylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl- 498* phenylamino)-benzamide 140A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid 490
S-phenethyl ester 141A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid 506
S-phenethyl ester 142A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid 536
S-benzyl ester 143A 2-(4-lodo-2-methyl-phenylamino)-5-nitro-thiobenzoic acid 503
S-benzyl ester 144A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid 476
S-benzyl ester 145A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid 492
S-benzyl ester 146A N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 409 benzamide Example Compound MS
No. M-H
147A 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- ' 429 phenylamino)-benzamide 148A 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 413 phenylamino)-benzamide 149A N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 475 benzamide 150A N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- 593* benzamide 151 A 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl- 567 benzyl)-benzamide 152A 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 473 phenylamino)-benzamide 153A N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl- 521 phenylamino)-benzamide 154A N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 440
5-nitro-benzamide 155A 2-(4-lodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- 486 benzamide 156A 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- 425 benzamide 157A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N- 459 phenyl-benzamide 158A N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 409 159A N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 583 benzamide 160A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- 538 benzyl)-benzamide 161A N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)- 425 benzamide 162A N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 436 benzamide 163A 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- 469 benzamide Example Compound MS
No. M-H
164A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N- 475 phenyl-benzamide 165A 5-lodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- 646 benzyl)-benzamide 166A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- 598 benzyl)-benzamide 167A N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 436 168A 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl- 565 benzyl)-benzamide 169A N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)- 469 benzamide 170A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl- 473 benzyl)-benzamide 171 A N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 517 benzamide 172A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N- 519 phenyl-benzamide 173A N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 502 benzamide 174A N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 559 benzamide 175A N-Allyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 517 176A 5-lodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl- 581 benzyl)-benzamide 177A 2-(4-lodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- 500
5-nitro-benzamide 178A 5-lodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 567 benzamide 179A N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 451 benzamide 180A 5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- 467 benzamide 181 A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl- 533 benzyl)-benzamide Example Compound MS
No. M-H
182A 5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- 511 benzamide 183A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl- 489 benzyl)-benzamide 184A N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 478 benzamide 185A N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- 538 benzamide 186A N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 477 benzamide 187A 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 431 phenylamino)-benzamide 188A 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 475 phenylamino)-benzamide 189A 2-(4-lodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- 488 benzamide 190A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N- 477 phenyl-benzamide 191 A N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl- 523 phenylamino)-benzamide 192A 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- 425 benzamide 193A N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)- 427 benzamide 194A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N- 461 phenyl-benzamide 195A N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 442
5-nitro-benzamide 196A 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 415 phenylamino)-benzamide 197A 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- 472 benzamide 198A N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 411 benzamide Example Compound MS No. M-H
199A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- 540 benzyl)-benzamide 200A N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 438 benzamide 201 A N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 411 202A N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 585 benzamide 203A N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)- 472 benzamide 204A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- 601 benzyl)-benzamide 205A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N- 522 phenyl-benzamide 206A N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 438
M+H
EXAMPLE 207A Preparation of [4-Chloro-2-(1 H-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)-amine
Step a: Preparation of 5-Chloro-2-fluoro-benzaldehvde
To a solution of 1-chloro-4-fluorobenzne (13.06 g, 0.1 mol) in THF (180 mL), at -78°C, LDA (2 M solution in THF, 50 mL, 0.1 mol) was added dropwise. 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:
1 H NMR (CDCI3): δ, 10.3 (s, -C(=O)H). Step b: Preparation of 5-Chloro-2-fluoro-benzaldehvde oxime
A solution of 5-chloro-2-fluoro-benzaldehyde (10 g, 0.0631 mol), hydroxylamine hydrochloride (6.57 g, 0.0946 mol) and pyridine (8.3 mL, 0.1010 mol) in EtOH (100 mL) was heated at 75°C (oil bath temperature) for 1 hour and the solvent removed under vacuum to give an oil. The oil was partitioned between water and CH2CI2. The CH2CI2 layer was dried (MgSO4) and the solvent removed under vacuum to give crude aldoxime as a solid. The solid was purified by medium pressure liquid chromatography on silica. Elution with CH2CI2 gave 4.87 g (28%) of the aldoxime as white solid: mp 95-97°C; Analysis calculated for C7H5NOFCI:
C, 48.44; H, 2.90; N, 8.07. Found: C, 48.55; H, 2.69, N, 7.90.
Step c: Preparation of 5-Chloro-2-fluoro-benzonirile
A solution of the 5-chloro-2-fluoro-benzaldehyde oxime (3.15 g, 0.0182 mol) in acetic anhydride (150 mL) was refluxed for 16 hours. The reaction mixture was cooled to room temperature and poured into saturated aqueous NaHCθ3 (200 mL) solution. The mixture was extracted with Et2θ.
The E_2θ 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)-1 H-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, E_2θ (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. HCI. 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)-1 H-tetrazole: mp partial melt at 110°C, complete melting at 124°C); H (400 Mz, CDCI3): δ 8.19-8.08 (m, 1H), 7.77-7.71 (m, 1 H), 7.61-7.52 (m,
1 H); 1 c (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 (Cl) M+1 = 199 (100), M = 198 (6).
Step e: Preparation of f4-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 1 -(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 CH2Cl2->CH2Cl2:MeOH (9.7:0.3) gave 1.5 g (48%) of the desired product: mp 205-208; 1 H (400 Mz, DMSO): δ 9.13 (s, 1 H), 8.00-7.99 (s, 1 H), 7.69 (s, 1 H), 7.55-7.52 (m, 1 H), 7.43-7.40 (m, 1H), 7.12-7.05 (m, 1 H), 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 (Cl) M+2 = 413 (44), M+1 = 412 (85), M = 411 (100).
Analysis calculated for C14H11 N5CII O.5H2O:
C, 39.97; H, 2.87; N, 16.65. Found: C, 38.87, H, 2.77; N, 16.47.
The following tetrazole substituted phenylamines were prepared by following the general procedure of Example 207A. EXAMPLE 208A ,4-lodo-2-methyl-phenyl.-.2-, 1 H-tetrazol-5-yl.-phenyllamine, mp 231 °C (dec)
EXAMPLE 209A r4-Nitro-2-(1 H-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)-amine. mp 205-208°C.
EXAMPLES 210A-224A
Additional invention compounds which were prepared by the general methods described above are:
Example Compound MP °C
No. 210A 2-(2-Chloro-4-iodo-phenylamino)-3-fluoro-4-(2- 239-241 morpholin-4-yl-ethylamino)-5-nitro-benzoic acid DEC
211A 4-Amino-2-(2-chloro-4-iodo-phenylamino)-3- >270 fluoro-5-nitro-benzoic acid 212A 2,4-Bis-(2-chloro-4-iodo-phenylamino)-3-fluoro- >265 DEC
5-nitro-benzoic acid 213A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-5- 218-225 nitro-benzoic acid DEC
214A 2-(2,6-Difluoro-4-iodo-phenylamino)-3,4- 247-249 difluoro-benzoic acid 215A 2-(2-Chloro-4-iodo-phenylamino)-4-nitro- 267-269 benzoic acid 216A 2-(2,4-Diiodo-phenylamino)-4-fluoro-benzoic 260-261 acid 217A 2-(2-Bromo-4-iodo-phenylamino)-4-fluoro- 259-262 benzoic acid 218A 4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)- 215-217 benzoic acid Example Compound MP °C
No. 219A 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro- 242-247 benzoic acid 220A 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4- 312.5-318 difluoro-benzoic acid 221A 2,3,5-Trifluoro-6-(4-iodo-2-methyl-phenylamino)- 118-121
4-(4-methyl-piperazin-1-yl)-benzoic acid methyl ester dihydrofluoride salt 222A 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 214-217 phenylarnino)-N-(4-methyl-piperazin-1 -yl)- DEC benazmide 223A 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 154-175 phenylamino)-benzoic acid N',N'-dimethyl- DEC hydrazide 224A 4-Fluoro-2-(4-iodo-2-methyl-phenylarnino)- 153.5-156 benzoic acid hydrazide
F. 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.
What is claimed is:

Claims

CLAIMS 1. A method for treating chronic pain, said method comprising administering to a subject in need of such treatment a composition comprising a MEK inhibitor selected from: a compound are defined by Formula I
wherein:
Ri is hydrogen, hydroxy, Ci-Cβ alkyl, Ci-Cg alkoxy, halo, trifluoromethyl, or CN; R2 is hydrogen; R3, R4, and R5 independently are hydrogen, hydroxy, halo, trifluoromethyl, Ci-Cg alkyl, Ci-Cs alkoxy, nitro, CN, or
(O or NH)m-(CH2)n-R9- where Rg is hydrogen, hydroxy, CO2H or NR10R11 ; n is 0 to 4; m is 0 or 1 ; Rl0 and Ri 1 independently are hydrogen or C -Cβ alkyl, or taken together with the nitrogen to which they are attached can complete a 3- to 10-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S, NH, or N-C1-C8 alkyl;
O
II
RQ is hydrogen, C1-C8 alkyl, C-C1-C8 alkyl, aryl, aralkyl, or C3-C10 cycloalkyl; R7 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl,
C3-C10 (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NRg); and wherein any of the foregoing alkyl, alkenyl, and alkynyl groups can be unsubstituted or substituted by cycloalkyl (or cycloalkyl optionally containing a heteroatom selected from O, S, or NRg), aryl, aryloxy, heteroaryl, or heteroaryloxy; or RQ and R7 taken together with the
N-0 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 NRI QRH -
2. The method of claim 1 , wherein said chronic pain is selected from neuropathic pain, idiopathic pain, and pain associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism.
3. The method of claim 2, wherein said chronic pain is a type of neuropathic pain.
4. The method of claim 3, wherein said neuropathic pain is associated with one of the following: inflammation, postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, viral infection, crush injury, constriction injury, tissue injury, limb amputation, post-operative pain, arthritis pain, and any other nerve injury between the peripheral nervous system and the central nervous system, inclusively.
5. The method of claim 2, wherein said chronic pain is associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism.
6. The method of claim 2, wherein said chronic pain is associated with idiopathic pain.
7. The method of claim 1 , wherein said chronic pain is associated with inflammation.
8. The method of claim 1 , wherein said chronic pain is associated with arthritis.
9. The method of claim 1 , wherein said chronic pain is associated with post-operative pain.
10. The method of claim 1 , wherein Ri is C1-C8 alkyl or halo.
11. The method according to claim 10 wherein RQ is hydrogen.
12. The method according to claim 11 wherein R is methyl.
13. The method according to claim 12 wherein the MEK inhibitor has the formula
O
14. The method of claim 13 wherein R4 is fluoro, and R3 and R5 are hydrogen.
15. The method of claim 14, wherein said MEK inhibitor 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; 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-N- isopropyl-benzamide; and
4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-N-methyl- benzamide.
16. The method of claim 13 wherein R3 and R4 are fluoro, and R5 is hydrogen.
17. The method of claim 16, wherein said MEK inhibitor has a structure selected from:
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;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydro- pyran-2-yloxy)-benzamide;
3,4-Difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide;
3,4-Difluoro-2-(2-chloro-4-iodo-phenylamino)-N- cyclobutylmethoxy-benzamide; 3,4-Difluoro-2-(2-chloro-4-iodo-phenylamino)-N-(tetrahydro- pyran-2-yloxy)-benzamide; and
3,4-Difluoro-2-(2-chloro-4-iodo-phenylamino)-N- cyclopropylmethoxy-benzamide.
18. The method of claim 13 wherein R3 and R4 are fluoro, and R5 is bromo.
19. The method according to claim 18, wherein said MEK inhibitor has a structure selected from:
5-Bromo-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (n-propoxy)-benzamide;
5-Bromo-3,4-difluoro-N-(furan-3-ylmethoxy)-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-N-(but-2-enyloxy)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide
5-Bromo-N-butoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-methyl-but-2-enyloxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-methyl-pent-2-en-4-ynyloxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-benzyl)-N- [5-(3-methoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-
2-ynyloxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- [3-(3-methoxy-phenyl)-prop-2-ynyloxy]-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (thiopen-2-ylmethoxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (pyridin-3-ylmethoxy)-benzamide;
5-Bromo-3-4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-(2-fluorophenyl)-prop-2-ynyloxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(ethoxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (isopropoxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-but- 3-ynyloxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2- piperidin-1-yl-ethoxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(tetrahydro-pyran-2-yloxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2- morpholin-4-yl-ethoxy)-benzamide;
5-Bromo-N-(2-diethylamino-ethoxy)-3,4-difluoro-(4-iodo-2- methyl-phenylamino)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- isobutoxy-benzamide;
5-Bromo-N-cyclohexylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-N-cyclopentylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-N-cyclobutylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N-(2-dimethylamino- ethoxy)-3,4-difluoro-benzamide monohydrochloride salt;
5-Bromo-N-(2-dimethylamino-propoxy)-3,4-difluoro — 2-(4-iodo- 2-methyl-phenylamino)-benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide;
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N- (tetrahydro-pyran-2-yloxy)-benzamide; and 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N- cyclopropylmethoxy-3,4-difluoro-benzamide.
20. The method of claim 13 wherein R3 and R4 are hydrogen, and R5 is halo.
21. The method according to claim 20, wherein said MEK inhibitor has a structure selected from:
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-lodo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide; and 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydropyran-
2-yloxy)-benzamide.
22. The method of claim 12 having the formula l(A):
1(A)
23. The method of claim 22 wherein R3 and R4 are fluoro, and R5 is hydrogen.
24. The method according to claim 23, wherein said MEK inhibitor has selected from:
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; and 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-
(cyclopentoxy)-benzamide.
25. The method according to claim 1 , wherein said MEK inhibitor has a structure selected from:
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;
4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide;
5-Chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide;
5-Bromo-2-(2-bromo-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-methyl- benzamide;
2-(2-Bromo-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy- benzamide;
2-(2-Bromo-4-iodo-phenylamino)-5-chloro-3,4-difluoro-N- hydroxy-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide;
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide;
2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide;
2-(2-Bromo-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide;
N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide;
N-Cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro- benzamide; N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide;
5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N- cyclopropylmethoxy-3,4-difluoro-benzamide;
N-Cyclopropylmethoxy-2-(2-fluoro-4-iodo-phenylamino)-4-nitro- benzamide;
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4,5-trifluoro-benzamide;
5-Chloro-2-(2-chloro-4-iodo-phenylamino)-N- cyclopropylmethoxy-3,4-difluoro-benzamide;
5-Bromo-2-(2-bromo-4-iodo-phenylamino)-N-ethoxy-3,4-difluoro- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-ethoxy-4-nitro-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4,5-trifluoro-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-5-chloro-N- cyclopropylmethoxy-3,4-difluoro-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-nitro- benzamide;
N-Cyclopropylmethoxy-4-fluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide;
N-Cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide;
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 4-fluoro-benzamide;
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4-difluoro-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-
4-fluoro-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4-difluoro-benzamide; N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydro- pyran-2-yloxy)-benzamide;
3,4-Difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide
(HCI salt);
2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-(tetrahydro-pyran-2- yloxy)-benzamide;
2-(2-Chloro-4-iodo-phenylamino)-N-cyclobutylmethoxy-3,4- difluoro-benzamide;
2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-(tetrahydro- pyran-2-yloxy)-benzamide;
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N-(2-dimethylamino- ethoxy)-3,4-difluoro-benzamide monohydrochloride salt; 5-Bromo-N-(2-dimethylamino-propoxy)-3,4-difluoro-2-(4-iodo-
2-methyl-phenylamino)-benzamide;
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide;
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N- (tetrahydro-pyran-2-yloxy)-benzamide;
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4- difluoro-benzamide; and
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N- cyclopropylmethoxy-3,4-difluoro-benzamide.
26. A method for treating chronic pain, said method comprising administering to a subject in need of such treatment a composition comprising a MEK inhibitor selected from: a compound of Formula 1(A)
wherein:
Ri is hydrogen, hydroxy, Ci-Cδ alkyl, Ci-Cβ alkoxy, halo, trifluoromethyl, or CN; R2 is hydrogen;
R3, R4, and R5 independently are hydrogen, hydroxy, halo, trifluoromethyl, C1-C8 alkyl, Ci-Cs alkoxy, nitro, CN, or
-(O or NH)m -(CH2)n-R9, where Rg is hydrogen, hydroxy,
COOH, or NRioRn ; n is 0-4; m is 0 or 1 ;
Rl0 and Ri 1 independently are hydrogen or C1-C8 alkyl, or taken together with the nitrogen to which they are attached can complete a 3-10 member cyclic ring optionally containing 1 , 2, or 3 additional heteroatoms selected from O, S, NH, or N-C1-C8 alkyl;
Z is COOR7, tetrazolyl, CONR6R7, CONHNR10R11 , or CH2OR7;
RQ and R7 independently are hydrogen, Ci-Cs alkyl, C2-C8 alkenyl,
O
C2-C8 alkynyl, C - C -C8 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 RQ 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, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, and the pharmaceutically acceptable salts thereof.
27. The method of claim 26, wherein said chronic pain is selected from neuropathic pain, idiopathic pain, and pain associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism.
28. The method of claim 27, wherein said chronic pain is a type of neuropathic pain.
29. The method of claim 28, wherein said neuropathic pain is associated with one of the following: inflammation, postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, viral infection, crush injury, constriction injury, tissue injury, limb amputation, post-operative pain, arthritis pain, and any other nerve injury between the peripheral nervous system and the central nervous system, inclusively.
30. The method of claim 27, wherein said chronic pain is associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism.
31. The method of claim 27, wherein said chronic pain is associated with idiopathic pain.
32. The method of claim 26, wherein said chronic pain is associated with inflammation.
33. The method of claim 26, wherein said chronic pain is associated with arthritis.
34. The method of claim 26, wherein said chronic pain is associated with post-operative pain.
35. The method of claim 26, wherein Ri is CH3 or halo.
36. The method according to claim 35 wherein Z is COOR7, tetrazolyl, or a salt thereof.
37. The method according to claim 36, wherein said MEK inhibitor has a structure selected from:
[4-Chloro-2-(1 H-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)-amine; (4-lodo-2-methyl-phenyl)-[2-(1 H-tetrazol-5-yl)-phenyl]amine; and [4-Nitro-2-(1 H-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)-amine.
38. The method according to claim 35 having the formula
39. The method of claim 38 wherein R3 is hydrogen, fluoro, or chloro; R4 is hydrogen, fluoro, chloro, or nitro; and R5 is hydrogen, chloro, fluoro, bromo, nitro, or methoxy.
40. The method of claim 39, wherein said MEK inhibitor has a structure selected from: 4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid; 3,4, 5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; Sodium 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoate;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
2-(4-lodo-2-methyl-phenylamino)-5-nitro-benzoic acid;
4-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
2-(4-lodo-2-methyl-phenylamino)-benzoic acid; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
5-lodo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
2,3,5-Thfluoro-4-(4-iodo-2-methyl-phenylamino)-benzoic acid;
2-(4-lodo-phenylamino)-5-methoxy-benzoic acid;
5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2-(4-lodo-2-methyl-phenylamino)-4-nitro-benzoic acid;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzoic acid;
2,3,5-Trifluoro-6-(4-iodo-2-methyl-phenylamino)-4-(4-methyl-piperazin- 1-yl)-benzoic acid methyl ester dihydrofluoride salt;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-methyl-piperazin- 1-yl)-benazmide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid N',N'- dimethyl-hydrazide; and
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide.
41. The method of claim 35 having the formula
42. The method of claim 41 wherein R3 is hydrogen, chloro, or fluoro; R4 is hydrogen, chloro, fluoro, or nitro; R5 is hydrogen, chloro, fluoro, bromo, nitro, or methoxy.
43. The method of claim 26, wherein said MEK inhibitor has a structure selected from:
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;
2-(2-Chloro-4-iodo-phenylamino)-3-fluoro-4-(2-morpholin-4-yl- ethylamino)-5-nitro-benzoic acid;
4-Amino-2-(2-chloro-4-iodo-phenylamino)-3-fluoro-5-nitro-benzoic acid;
2,4-Bis-(2-chloro-4-iodo-phenylamino)-3-fluoro-5-nitro-benzoic acid;
2-(2-Chloro-4-iodo-phenylamino)-4-nitro-benzoic acid;
2-(2,4-Diiodo-phenylamino)-4-fluoro-benzoic acid; 2-(2-Brorno-4-iodo-phenylamino)-4-fluoro-benzoic acid;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid;
2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-benzoic acid; and
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid.
44. The method of claim 35 wherein Z is CONR6R7.
45. The method of claim 44 having the formula
O
46. The method of claim 45 wherein R3 is hydrogen, chloro, or fluoro; R4 is hydrogen, chloro, fluoro, or nitro; and R5 is hydrogen, chloro, fluoro, bromo, nitro, or methoxy.
47. The method of claim 46, wherein said MEK inhibitor has a structure selected from:
5-Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-benzamide; N-Ethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(1 H-tetrazol-5-yl)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide;
[5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoylamino]-acetic acid; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-propyl-benzamide; 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
4-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-2-(4-iodo-
2-methyl-phenylamino)-benzamide; N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; N-Butyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-N,N-diethyl-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide; 5-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-(2,3-Dihydroxy-propyl)-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- 1 -yl-ethyl)-benzamide; 3,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-(2,3-Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 3,4-Difluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-
1 -yl-ethyl)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin- 4-yl-ethyl)-benzamide;
4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-N-(3-dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-
4-yl-ethyl)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- ethyl)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl- ethyl)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl-ethyl)- benzamide; N-(3-Dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-Benzyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethyl)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-propyl)- benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl- propyl)-benzamide; -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thiophen-2-yl-ethyl)- benzamide; -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)- benzamide; -(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-morpholin-4-yl- ethyl)-benzamide; -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-
4-ylmethyl-benzamide; ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide; -(4-Bromo-2-methyl-phenylamino)-N-(3-dimethylamino- propyl)-3,4-difluoro-benzamide; -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide; -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl-ethyl)- benzamide; -(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyhdin-4-yl-ethyl)- benzamide; -(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(3-hydroxy-propyl)- benzamide; -(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyrrolidin-1-yl- ethyl)-benzamide; -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyl-benzamide; -(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-thiophen-2-yl- ethyl)-benzamide; -(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-pyhdin-4-ylmethyl- benzamide; -(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-phenethyl- benzamide; -(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-piperidin-1-yl- ethyl)-benzamide; -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-lodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl methyl- benzamide; 5-Bromo-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-2-(4-iodo-
2-methyl- phenylamino)- benzamide; 5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl-ethyl)- benzamide;
(3-Hydroxy-pyrrolidin-1-yl)-[2-(4-iodo-2-methyl-phenylamino)-5-nitro- phenyl]; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)- benzamide; 5-Bromo-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-chloro-2-(4-iodo-2-methyl- phenylamino)- benzamide; N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-bromo-2-(4-iodo-2-methyl- phenylamino)- benzamide;
N-{3-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-propyl}-2-(4-iodo-2-methyl- phenylamino)- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide; 5-Bromo-2-(4-iodo-2-ethyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl-ethyl)- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-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-lodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin-1-yl-ethyl)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin-1-yl-ethyl)- benzamide; N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; 5-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-(3-Diethylamino-propyl)-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-(3-Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)- benzamide; 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin-1-yl-propyl)- benzamide;
[5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(3-hydroxy- pyrrolidin-1-yl)-; 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-;
N-(3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)- benzamide; N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide; 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-(2-Hydroxy-ethyl)-2-(4-iodo-2-ethyl-phenylamino)-5-nitro-benzamide; 2-(4-lodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- benzamide;
5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide; N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; 5-lodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-suϊfamoyl-benzyl)- benzamide; N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; 2-(4-lodo-
2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide; N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide; N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 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-lodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide; 2-(4-lodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-5-nitro- benzamide; 5-lodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide;
5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide; N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 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-lodo-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; and N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide.
48. The method of claim 35 wherein Z is CH2OR7.
49. The method of claim 48 having the formula
50. The method of claim 49 wherein: R3 is hydrogen, chloro, or fluoro; R4 is hydrogen, chloro, fluoro, or nitro; and R5 is hydrogen, chloro, fluoro, bromo, nitro, or methoxy.
51. The method of claim 50 which is 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohol; [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol; [2-(4-lodo-2-methyl-phenylamino)-5-nitro-phenyl]-methanol; and [5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol.
52. The method of claim 1 , wherein said MEK inhibitor has a structure selected from:
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide; N-Cyclopropylmethoxy-3,4,5-trifuoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Cyclopropylmethoxy-3,4,5-trifuoro-2-(4-iodo-2-methyl-phenylamino)- benzamide, potassium salt; 2-(2-Chloro-4-iodo-phenylamino)-N-cyclobutylmethoxy-3,4-difluoro- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro- benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy- benzamide; 3,4-Difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide;
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide; N-Cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-N-cyclobutylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Chloro-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4- difluoro-benzamide; 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide, hydrochloride salt; 5-Bromo-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)- benzamide; 3,4-Difluoro-N-(2-hydroxy-ethoxy)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-(3-hydroxy- propoxy)-benzamide;
2-(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-N-(3-hydroxy-propoxy)- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-N-[2-(2-methoxy- ethoxy)-ethoxy]-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-(3-hydroxy-propoxy)- benzamide; 5-Bromo-3,4-difluoro-N-(3-hydroxy-propoxy)-2-(4-iodo-2-methyl- phenylamino)-benzamide; 3,4,5-Trifluoro-N-(3-hydroxy-propoxy)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
3,4,5-Trifluoro-N-(2-hydroxy-ethoxy)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)- benzamide; and 3,4-Difluoro-N-(2-hydroxy-ethoxy)-2-(4-iodo-2-methyl-phenylamino)- benzamide.
53. The method of claim 1 , wherein said MEK inhibitor has a structure selected from: 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide; N-Cyclopropylmethoxy-3,4,5-trifuoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)- benzamide; and 3,4-Difluoro-N-(2-hydroxy-ethoxy)-2-(4-iodo-2-methyl-phenylamino)- benzamide.
54. The method of claim 26, wherein said MEK inhibitor has a structure selected from: 2-(2-Chloro-4-iodo-phenylamino)-3,4difluoro-benzoic acid;
3,4, 5-Thfluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-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;
2-(2-Chloro-4-iodo-pyenylamino)-3,4-difluoro-5-nitro-benzoic acid;
2-(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-benzoic acid; 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)1 H-benzoimidazole-5- carboxylic acid cyclopropylmethoxy-amide;
5-Chloro-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; and
5-Chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid.
55. The method of claim 26, wherein said MEK inhibitor has a structure selected from:
2-(2-Chloro-4-iodo-phenylamino)-3,4difluoro-benzoic acid; and 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)1 H-benzoimidazole-5- carboxylic acid cyclopropylmethoxy-amide.
EP00943383A 1999-07-16 2000-07-05 Method for treating chronic pain using mek inhibitors Withdrawn EP1202726A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US14429299P 1999-07-16 1999-07-16
US144292P 1999-07-16
PCT/US2000/018347 WO2001005392A2 (en) 1999-07-16 2000-07-05 Method for treating chronic pain using mek inhibitors

Publications (1)

Publication Number Publication Date
EP1202726A2 true EP1202726A2 (en) 2002-05-08

Family

ID=22507940

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00943383A Withdrawn EP1202726A2 (en) 1999-07-16 2000-07-05 Method for treating chronic pain using mek inhibitors

Country Status (16)

Country Link
EP (1) EP1202726A2 (en)
JP (1) JP2003504400A (en)
KR (1) KR20020012315A (en)
CN (1) CN1373660A (en)
AR (1) AR024732A1 (en)
AU (1) AU5786000A (en)
CA (1) CA2374052A1 (en)
CO (1) CO5300398A1 (en)
HU (1) HUP0202623A3 (en)
IL (1) IL147619A0 (en)
NZ (1) NZ515567A (en)
PE (1) PE20010545A1 (en)
PL (1) PL352684A1 (en)
TR (1) TR200200082T2 (en)
WO (1) WO2001005392A2 (en)
ZA (1) ZA200109907B (en)

Families Citing this family (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DZ3401A1 (en) 2000-07-19 2002-01-24 Warner Lambert Co OXYGEN ESTERS OF 4-IODOPHENYLAMINO BENZHYDROXAMIC ACIDS
IL149462A0 (en) 2001-05-09 2002-11-10 Warner Lambert Co 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
SI1482932T1 (en) 2002-03-13 2010-02-26 Array Biopharma Inc N3 alkylated benzimidazole derivatives as mek inhibitors
US7632866B2 (en) 2002-10-21 2009-12-15 Ramot At Tel Aviv University Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators
ES2331246T3 (en) 2003-07-24 2009-12-28 Warner-Lambert Company Llc DERIVATIVES OF BENZAMIDAZOL AS INHIBITORS OF THE MEK.
US7538120B2 (en) 2003-09-03 2009-05-26 Array Biopharma Inc. Method of treating inflammatory diseases
US7144907B2 (en) 2003-09-03 2006-12-05 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
EP1676837A4 (en) * 2003-10-08 2008-09-10 Teijin Pharma Ltd Process for producing aminopyrrolidine derivative and intermediate compound
RU2352558C2 (en) 2003-10-21 2009-04-20 Уорнер-Ламберт Компани Ллс Polymorphic form of n-[(r)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide
US7732616B2 (en) 2003-11-19 2010-06-08 Array Biopharma Inc. Dihydropyridine and dihydropyridazine derivatives as inhibitors of MEK and methods of use thereof
US7517994B2 (en) 2003-11-19 2009-04-14 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
AU2004293436B2 (en) 2003-11-19 2010-12-09 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
CN1882347A (en) 2003-11-21 2006-12-20 阿雷生物药品公司 AKT protein kinase inhibitors
TWI361066B (en) * 2004-07-26 2012-04-01 Chugai Pharmaceutical Co Ltd 5-substituted-2-phenylamino benzamides as mek inhibitors
DK1922307T3 (en) 2005-05-18 2012-04-02 Array Biopharma Inc Heterocyclic Inhibitors of MEK and Methods for Using Them
CA3052368A1 (en) 2005-10-07 2007-04-19 Exelixis, Inc. Azetidines as mek inhibitors
US8063050B2 (en) 2006-07-06 2011-11-22 Array Biopharma Inc. Hydroxylated and methoxylated pyrimidyl cyclopentanes as AKT protein kinase inhibitors
US9303040B2 (en) 2006-07-06 2016-04-05 Array Biopharma Inc. Substituted piperazines as AKT inhibitors
CA2656618C (en) 2006-07-06 2014-08-26 Array Biopharma Inc. Cyclopenta [d] pyrimidines as akt protein kinase inhibitors
JP5231410B2 (en) 2006-07-06 2013-07-10 アレイ バイオファーマ、インコーポレイテッド Dihydrofuropyrimidine as an AKT protein kinase inhibitor
CN105106199A (en) 2006-12-14 2015-12-02 埃克塞利希斯股份有限公司 Methods of using MEK inhibitors
US9409886B2 (en) 2007-07-05 2016-08-09 Array Biopharma Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
EP2173723B3 (en) 2007-07-05 2014-11-19 Array Biopharma Inc. Pyrimidyl cyclopentanes as akt protein kinase inhibitors
TWI450720B (en) 2007-07-05 2014-09-01 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
CN101868443A (en) 2007-09-20 2010-10-20 特拉维夫大学拉莫特有限公司 N-phenyl anthranilic acid derivatives and uses thereof
US8198279B2 (en) 2007-12-19 2012-06-12 Institute Of Cancer Research: Royal Cancer Hospital (The) Pyrido[2,3-b]pyrazin-8-substituted compounds and their use
EP2247578B1 (en) 2008-01-09 2013-05-22 Array Biopharma, Inc. Hydroxylated pyrimidyl cyclopentanes as akt protein kinase inhibitors
JP5539225B2 (en) 2008-01-09 2014-07-02 アレイ バイオファーマ、インコーポレイテッド Hydroxylated pyrimidylcyclopentane as an AKT protein kinase inhibitor
EP2346818B1 (en) 2008-11-10 2012-12-05 Bayer Intellectual Property GmbH Substituted sulphonamido phenoxybenzamides
CN102574782B (en) 2009-10-21 2014-10-08 拜耳知识产权有限责任公司 Substituted halophenoxybenzamide derivatives
WO2011047795A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted benzosulphonamides
US8962606B2 (en) 2009-10-21 2015-02-24 Bayer Intellectual Property Gmbh Substituted benzosulphonamides
AU2011209586B2 (en) 2010-02-01 2016-01-21 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
WO2012055953A1 (en) 2010-10-29 2012-05-03 Bayer Pharma Aktiengesellschaft Substituted phenoxypyridines
RS56759B1 (en) 2011-04-01 2018-04-30 Genentech Inc Combination of akt inhibitor compound and abiraterone for use in therapeutic treatments
EP2694073B1 (en) 2011-04-01 2018-08-08 Genentech, Inc. Combinations of akt and mek inhibitors for treating cancer
MY186549A (en) 2012-10-12 2021-07-26 Exelixis Inc Novel process for making compounds for use in the treatment of cancer
AU2014318748B2 (en) 2013-09-11 2019-02-28 Duquesne University Of The Holy Ghost Novel anthranilic amides and the use thereof
GB201320732D0 (en) 2013-11-25 2014-01-08 Cancer Rec Tech Ltd Methods of chemical synthesis
GB201320729D0 (en) 2013-11-25 2014-01-08 Cancer Rec Tech Ltd Therapeutic compounds and their use
EP3368026A1 (en) * 2015-10-27 2018-09-05 Acetylon Pharmaceuticals, Inc. Hdac inhibitors for the treatment of diabetic peripheral neuropathy
AU2018351475A1 (en) 2017-10-17 2020-04-30 Atriva Therapeutics Gmbh Novel mek-inhibitor for the treatment of viral and bacterial infections
WO2020259787A1 (en) * 2019-06-28 2020-12-30 University Of Copenhagen Treatment of cns disorders with sleep disturbances

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998037881A1 (en) * 1997-02-28 1998-09-03 Warner Lambert Company Method of treating or preventing septic shock by administering a mek inhibitor
EP0993439B1 (en) * 1997-07-01 2004-09-29 Warner-Lambert Company LLC 4-bromo or 4-iodo phenylamino benzhydroxamic acid derivatives and their use as mek inhibitors
WO1999001421A1 (en) * 1997-07-01 1999-01-14 Warner-Lambert Company 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives and their use as mek inhibitors
CA2346448A1 (en) * 1998-12-16 2000-06-22 Warner-Lambert Company Treatment of arthritis with mek inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0105392A2 *

Also Published As

Publication number Publication date
NZ515567A (en) 2004-03-26
TR200200082T2 (en) 2002-04-22
ZA200109907B (en) 2003-02-28
AU5786000A (en) 2001-02-05
WO2001005392A3 (en) 2001-07-19
JP2003504400A (en) 2003-02-04
KR20020012315A (en) 2002-02-15
PL352684A1 (en) 2003-09-08
CN1373660A (en) 2002-10-09
PE20010545A1 (en) 2001-06-04
WO2001005392A2 (en) 2001-01-25
IL147619A0 (en) 2002-08-14
CA2374052A1 (en) 2001-01-25
HUP0202623A3 (en) 2003-03-28
HUP0202623A2 (en) 2002-11-28
AR024732A1 (en) 2002-10-23
CO5300398A1 (en) 2003-07-31

Similar Documents

Publication Publication Date Title
WO2001005392A2 (en) Method for treating chronic pain using mek inhibitors
EP1202724B1 (en) Method for treating chronic pain using mek inhibitors
EP1202731A2 (en) Method for treating chronic pain using mek inhibitors
WO2001005391A2 (en) Method for treating chronic pain using mek inhibitors
AU776788B2 (en) Treatment of arthritis with MEK inhibitors
DE69928568T2 (en) CHEMOTHERIAPY WITH ANTIMITOTIC AGENT AND MEK INHIBITOR
JP2003527379A (en) 5-Amido-substituted diarylamines as MEX inhibitors
US20030225076A1 (en) 5-Amide substituted diarylamines as mex inhibitors
JP2002534515A (en) 1-heterocyclic-substituted diarylamines
JP2002332247A (en) Method for treating or inhibiting chemotaxis of neutrophil by administering mek inhibitor
CA2350234A1 (en) Treatment of asthma with mek inhibitors
JP2002532415A5 (en) Therapeutic pharmaceutical composition for arthritis containing a MEK inhibitor
US7030119B1 (en) Method for treating chronic pain using MEK inhibitors
US20040171632A1 (en) Combination chemotherapy
ZA200109909B (en) Method for treating chronic pain using MEK inhibitors.
MXPA01005476A (en) Combination chemotherapy

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20020218

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

17Q First examination report despatched

Effective date: 20020722

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: WARNER-LAMBERT COMPANY LLC

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20051227