EP1202731A2 - Methode de traitement de la douleur chronique au moyen d'inhibiteurs de mek - Google Patents

Methode de traitement de la douleur chronique au moyen d'inhibiteurs de mek

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Publication number
EP1202731A2
EP1202731A2 EP00947013A EP00947013A EP1202731A2 EP 1202731 A2 EP1202731 A2 EP 1202731A2 EP 00947013 A EP00947013 A EP 00947013A EP 00947013 A EP00947013 A EP 00947013A EP 1202731 A2 EP1202731 A2 EP 1202731A2
Authority
EP
European Patent Office
Prior art keywords
methyl
fluoro
phenylamino
iodo
alkyl
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Withdrawn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
EP00947013A
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German (de)
English (en)
Inventor
Stephen Douglas Barrett
Alexander James Bridges
Haile Tecle
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
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Warner Lambert Co LLC
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Publication of EP1202731A2 publication Critical patent/EP1202731A2/fr
Withdrawn legal-status Critical Current

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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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Definitions

  • 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.
  • 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.PediatrMed.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 compositions 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 USSN 60/115,873, filed January 13, 1999, PCT/US99/30483, international filing date December 21 , 1999.
  • MEK inhibitors include a compound having the formula (I) below:
  • W is ORi, NR 2 OR ⁇ , NR A R B , NR 2 NR A R B , 0(CH 2 ) 2-4 NR A R B , or NR 2 (CH 2 ) 2 .4 NR A RB- RI is H, C ⁇ -8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 3-8 cycloalkyl, phenyl, (phenyl)C 1 ⁇ alkyl, (phenyl)C 3- alkenyl, (phenyl)C 3-4 alkynyl, (C 3-8 cycloalkyl)C 1 ⁇ alkyl, (C 3-8 cycloalkyI)C 3-4 alkenyl, (C 3-8 cycloalkyl)C 3- alkynyl, C 3-8 heterocyclic radical, (C 3- s heterocyclic radical)C ⁇ - alkyl, (C 3-8 heterocyclic radical)C 3- alkenyl,
  • R 3 is H or F;
  • R 4 is halo, N0 2 , S0 2 NR 0 (CH 2 ) 2-4 NR E RF, S0 2 NR E R F or (CO)T.
  • T is C ⁇ -8 alkyl, C 3-8 cycloalkyl, (NR E R F )C i-4 alkyl, OR F , -NR 0 (CH 2 ) 2-4 NR E R F , or NR E R ;
  • Z is one of the following formulae (iv) - (viii):
  • R 5 and R 6 is H or methyl and the other of R and R 6 is H, C 1 - 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, benzyl, or -M-E-G.
  • M is O, CO, S0 2 , NR Jf (CO)NRH, NR H (CO), NR H (S0 2 ). (S0 2 )NR H , or CH 2 .
  • E is (CH 2 ) 1-4 or (CH 2 ) m 0(CH 2 ) p where 1 ⁇ (each of m and p) ⁇ 3 and 2 ⁇ (m + p) ⁇ 4; or E is absent.
  • R 7 is H, C 1-4 alkyl, C 2- alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, (CH 2 ) 1-2 Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, S0 2 NRH(CH 2 ) 2-4 NRJRK, (CO)(CH 2 ) 2-4 NRjR ⁇ or (CO)NRH(CH 2 ) 2 -4NRJRK.
  • XI is O, S, NR 8 , or CHR 9 ;
  • X 2 is O, S, or CHR 9 ; and
  • X 3 is O or S.
  • the disclosed compound may also be a tautomerized indole.
  • R 8 is H, C ⁇ alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, (CH 2 ) ⁇ -2 Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, C 2 -4 alkenyl, C 2- ⁇ alkynyl, C 3-6 cycloalkyl, or (C 2 -A alkyl)NR L R ⁇ v ⁇ provided R 7 and R 8 together have no more than 14 carbon atoms, exclusive of R , RM, RJ and R «.
  • R G is C 1-4 alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C 3-4 alkenyl, C 3-4 alkynyl, C 3-6 cycloalkyl, (CO)OR P , (C 2-4 alkyl)NR L R,v ⁇ , (CO)NR N (CH 2 ) 2- NR L R M , (CO)NRLR , (CO)(CH 2 ) 2 -4 -NR L R , or (CH 2 ) ⁇ -2 Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.
  • R 9 is C 1 - 4 alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, (CO)OR P , (C 2- ⁇ alkyl)NR L R M , (CO)NR N (CH 2 ) 2 ⁇ NR L R , (CO)NR L R M , (CO)(CH 2 ) 2-4 - NRLRM, or (CH 2 ) 1-2 Ar', where Ar' is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.
  • Rp is H, C 1- 6 alkyl, phenyl, C 3-4 alkenyl, C 3-4 alkynyl, C 3-6 cycloalkyl, or
  • RIO is H, methyl, halo, or N0 2
  • Rn is H, methyl, halo, or N0 2
  • R c , RD, RE, RF, RI, RJ, RK, RL and R M is independently selected from H, C 1-4 alkyl, C 3- alkenyl, C 3- alkynyl, C 3-6 cycloalkyl, and phenyl
  • each of NRCRD, NR E R F , NRJR K , and NR RM can also independently be morpholinyl, piperazinyl, pyrrolidinyl, or piperadinyl.
  • each of RH, RN, and R 0 is independently H, methyl, or ethyl.
  • each hydrocarbon radical or heterocyclic radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, C 1.4 alkyl, C 3-6 cycloalkyl, C 2 - 4 alkenyl, C 2-4 alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, and N0 2 , wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally substituted with between 1 and 3 substituents independently selected from halo, C ⁇ -2 alkyl, hydroxyl, amino, and N0 2 .
  • the invention also provides a pharmaceutically-acceptable salt or C ester thereof.
  • Preferred embodiments of the invention include methods using one or more of the following compounds:
  • said MEK inhibitor has a structure selected from: 7-fluoro-6-(4-iodo-2- methyl-phenylamino)-1 H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide; 7-fluoro-6-(4-iodo-2-methyl-phenyiamino)-6,7- dihydro-1H-benzoimidazole-5-carboxylic acid (hydrochloride); 7-fluoro-6-(4- iodo-2-methyl-phenylamino)-1 /-/-benzoimidazole-5-carboxylic acid; 7-fluoro-6- (4-iodo-2-methyl-phenylamino)-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide; 6-(2-chloro-4-iodo-phenylamino)-7-fluoro-1 - - benzoimidazole-5-carbox
  • the invention also relates to a pharmaceutical composition including (a) a benzoheterocycle (e.g., of formula I) and (b) a pharmaceutically- acceptable carrier.
  • a benzoheterocycle e.g., of formula I
  • a pharmaceutically- acceptable carrier e.g., of formula I
  • 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.
  • 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 (1-30 ⁇ g/10 ⁇ l), or pregabalin (100 ⁇ g/10 ⁇ l) and withdrawal thresholds were re-assessed at 30min, 1 h and 2h after treatment. Results are expressed median ⁇ 1 st and 3 rd quartiles.
  • 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.
  • 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.
  • 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.
  • 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 (ERK1 and ERK 2 ).
  • MEK e.g., MEKi and MEK2
  • MAP kinase e.g., MAP kinase
  • ERK ERK1 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 j s222 j n 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, Y 1 85 and a threonine residue, T 1 ⁇ 3 separated by a single amino acid.
  • 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.
  • 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- 30 ⁇ g) dose-dependently blocked static allodynia in both the streptozocin and the CCI models of neuropathic pain, with minimum effective doses (MED) of 3 and 10 ⁇ g respectively. The highest dose used (30 ⁇ g) totally blocked the maintenance of static allodynia, for up to 1h.
  • MED minimum effective doses
  • 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 2-4 or C 2 - 8 , for example, and are preferably C 3 . 4 or C 3 . 8 .
  • 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.
  • R 1 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 50 for one of the above-named other enzymes.
  • a selective inhibitor has an IC 50 that is at least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/5000, or less than that of its IC 50 or one or more of the above-named enzymes.
  • Embodiments of the invention includes compounds of formula (I) wherein: (a) Q is formula (i); (b) R 3 is H or fluoro; (c) R is fluoro, chloro, or bromo; (d) R 10 is H, methyl, fluoro, or chloro; (e) Rn is methyl, chloro, fluoro, nitro, or hydrogen; (f) Rn is H; (g) Rn is fluoro; (h) each of R-io and Rn is fluoro; (i) Ri is H, methyl, ethyl, propyl, isopropyl, isobutyl, benzyl, phenethyl, allyl, C 3-5 alkenyl, C 3-6 cycloalkyl, (C 3-5 cycloalkyl)C ⁇ -2 alkyl, (C 3-5 heterocyclic radical)C ⁇ -2 alkyl
  • the compound of formula (I) has a structure wherein: Q is formula (i) or (ii); R 3 is H or fluoro; R 4 is fluoro, chloro, or bromo; R ⁇ 0 is H, methyl, or chloro; R is chloro, fluoro, or hydrogen; Ri is H, methyl, ethyl, propyl, isopropyl, isobutyl, benzyl, phenethyl, allyl, C 3-5 alkenyl, C 3-6 cycloalkyl, (C 3-5 cycloalkyl)C ⁇ -2 alkyl, (C 3-5 heterocyclic radical)C ⁇ -2 alkyl, or (CH 2 ) 2 -4 NR C RD; RI is H or (C 3- 4 cycloalkyl)C ⁇ -2 alkyl; R 2 is H or methyl; and Z is formula (v) or (vi).
  • Xi is NR 8
  • An example would be 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1[(2'- morpholinyl)-ethyl]-2-(phenyl)-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide.
  • Embodiments of the invention also include compounds wherein Rio is H; Rio is methyl or chloro; and where Rio is chloro.
  • R 7 and R 8 together have no more than 14 carbon atoms, exclusive of R L , RM, RJ and R ⁇ . Examples of this include compounds wherein R and R 8 together have no more than 13 carbon atoms; no more than 7, 8, or 10 carbon atoms; between 4 and 8 carbon atoms; between 1 and 10 carbon atoms; between 1 and 8 carbon atoms; and no more than 6 carbon atoms.
  • Ri, R 2 , R A , R B , Re, RD, RE, RF, RI, RJ, RK, RL , RM, RG, RH, RN, R O , and Rp is an alkenyl or alkynyl group, its double or triple bond, respectively, is not adjacent the point of attachment.
  • W is NR 2 OR ⁇
  • R 2 is preferably prop-2-ynyl, or but-2 or 3-enyl, and less preferably prop-1-ynyl or but-1-enyl.
  • Examples of compounds from schemes 3-9 include: 4-Fluoro-5-(4- iodo-2-methyl-phenylamino)-benzothiazole-6-carboxylic acid; 4-Fluoro-5-(4- iodo-2-methyl-phenylamino)-benzooxazole-6-carboxylic acid; 5-(2-Chloro-4- iodo-phenylamino)-6,7-difluoro-3H-benzoimidazole-4-carboxylic acid; 6,7- Difluoro-2-(2-hydroxy-ethyl)-5-(4-iodo-2-methyl-phenylamino)-3H- benzoimidazole-4-carboxylic acid; 6,7-Difluoro-5-(4-iodo-2-methyl- phenylamino)-benzooxazole-4-carboxylic acid; 6,7-Difluoro-5-(4-iodo-2-methyl-
  • the disclosed compounds can be synthesized according to the following eleven Schemes, or variants thereof. These synthetic strategies are further exemplified in Examples 1-22 below.
  • 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, intraperitoneal, 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 accelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and (j) 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 1-6 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 ⁇ -3 alkyl primary amines, and di (C ⁇ -2 alkyl)amines.
  • Representative pharmaceutically acceptable esters of the invention include C 1-7 alkyl, C 5 - 7 cycloalkyl, phenyl, and phenyl(C ⁇ -6 )alkyl 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"-tris(
  • Silyl Ethers Silyl ethers include: trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, -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, t phenylmethoxyacetate, 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: methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl) ethyl, 2-(phenylsulfonyl) ethyl, 2-(triphenylphosphonio) ethyl, isobutyl, vinyl, allyl, 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-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2- butenoate (tigloate), o-(methoxycarbonyl) benzoate, p-P-benzoate, ⁇ -naphthoate, nitrate, alkyl N,N,N ' ⁇ / '-tetramethylphosphorodiamidate, ⁇ /-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, ⁇ -(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-(thmethylsilyl)ethoxy-methyl, benzyloxymethyl, phenacyl, p-bromophenacyl, ⁇ -methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N- phthalimidomethyl.
  • 2-Substituted Ethyl Esters include: 2,2,2-trichloroethyl, 2-haloethyl, ⁇ - chloroalkyl, 2-(trimethylsily)ethyl, 2-methylthioethyl, 1 ,3-dithianyl-2-methyl, 2(p-nitrophenylsulfenyl)-ethyl, 2-(p-toluenesulfonyl)ethyl, 2-(2'-py dyl)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
  • Substituted Benzyl esters include: triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5- dibenzo-suberyl, 1-pyrenylmethyl,2-(thfluoromethyl)-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- f-butylmethylsilyl.
  • 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-f-butyl-[9-(10,10- dioxo-10,10,10,10-tetrahydro- thioxanthyl)]methyl, and 4-methoxyphenacyl.
  • Substituted Ethyl protective groups include: 2,2,2-trichloroethyl, 2- trimethylsily lethyl , 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1 ,1-dimethyl- 2-haloethyl, 1 ,1dimethyl-2,2-dibromoethyl, 1 ,1-dimethyl-2,2,2-thchloroethyl, 1- methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di- ⁇ -butylphenyl)-1-methylethyl, 2-(2'-and 4'-pyridyl)ethyl, 2-( ⁇ /, ⁇ /-icyclohexylcarboxamido)- ethyl, .-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, connamy
  • Protection via assisted cleavage includes: 2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1 ,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethyl-thiophenyl, 2-phosphonioethyl, 2-thphenylphosphonioisopropyl, 1 ,1-dimethyl-2cyanoethyl, m-chloro-p- acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolyl-methyl, and 2-(trifluoromethyl)-6-chromonylmethyl. Photolvtic Cleavage
  • Photolytic 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, ⁇ /-o- (benzoyloxymethyl)benzoyl, and 4,5-diphenyl-3-oxazolin
  • 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 include: ⁇ /-methyl, ⁇ /-allyl,
  • Imine derivatives include: ⁇ /-1 ,1-dimethylthiomethylene, ⁇ /-benzylidene, ⁇ /-p-methoxybenzylidene, ⁇ /-diphenylmethylene,
  • ⁇ /-metal derivatives include: ⁇ /-borane derivatives, ⁇ /-diphenylborinic acid derivative, ⁇ /-[phenyl(pentacarbonylchromium- or -tungsten)]carbenyl, and
  • N-N derivatives include: ⁇ /-nitro,
  • ⁇ /-N ⁇ /-nitroso, and ⁇ /-oxide.
  • ⁇ /-P derivatives include:
  • ⁇ /-sulfenyl derivatives examples include: ⁇ /-benzenesulfenyl,
  • ⁇ /-triphenylmethylsulfenyl and ⁇ /-3-nitropyridinesulfenyl.
  • ⁇ /-sulfonyl derivatives include: ⁇ /-p-toluenesulfonyl, ⁇ /-benzenesulfonyl,
  • 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.
  • Diabetes was induced in rats by a single i.p. injection of streptozocin (50mg/kg) as described previously (Courteix et al., 1993).
  • 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, 1 h 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, 1 h, 2h and 3h after administration for streptozocin treated animals. CCI animals were assessed before, 1h 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, 1h and 2h after intrathecal administration of the compounds
  • 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.
  • Step a Preparation of 5-nitro-2,3,4-trifluorobenzoic acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3 x 200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid.
  • Step c Preparation of methyl 4-amino-2,3-difluoro-5-nitrobenzoate Hydrogen chloride gas was dissolved in anhydrous methanol (30 ml) until the solution was warm. The solid 4-amino-2,3-difluoro-5-nitrobenzoic acid (0.47 g; 0.00215 mol) was dissolved in this solution and the reaction mixture was brought to reflux with vigorous stirring for 23 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool slowly on the bench. A yellow precipitate formed and was collected by vacuum filtration and dried with suction to afford 0.35 g of yellow microfilaments; 70 % yield; m.p.
  • Step d Preparation of methyl 4-amino-3-fluoro-2-(2-methyl-phenylamino)-5- nitrobenzoate
  • the solid methyl 4-amino-2,3-difluoro-5-nitrobenzoate (0.087 g, 3.7 x lO ⁇ mol) was dissolved in ortfto-toluidine (3 ml, 0.028 mol).
  • the reaction mixture was stirred at 200 °C for 35 minutes under a nitrogen atmosphere.
  • the mixture was then partitioned between diethyl ether (150 ml) and 10 % aqueous hydrochloric acid (150 ml).
  • the ether phase was dried with anhydrous magnesium sulfate and was concentrated in vacuo to a crude solid.
  • Step e Preparation of methyl 4.5-diamino-3-fluoro-2-(2-methyl- phenylamino)benzoate
  • Step f Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino)-1 H- benzoimidazole-5-carboxylate
  • the filtrate was concentrated in vacuo to a crude solid which was triturated with 10 ml of chloroform-dichloromethane.
  • Step g Preparation of methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzoimidazole-5-carboxylate
  • a stirring mixture comprised of methyl 7-fluoro-6-(2-methyl- phenylamino)-1 H-benzoimidazole-5-carboxylate (0.2492 g, 8.326 x 10 "4 mol), benzyltrimethylammonium dichloroiodinate (Aldrich, 95 %, 0.3934 g, 0.00113 mol), and zinc chloride (0.1899 g, 0.00139 mol) in glacial acetic acid (20 ml) was brought to reflux for 15 minutes. The hot suspension was filtered to isolate the precipitate which was dried in the vacuum oven (90 °C, ca. 10 mm Hg) overnight to afford 0.2392 g of a green powder; 68 % yield; m.p.
  • Step h Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzoimidazole-5-carboxylic acid
  • the off-white precipitate formed was collected by vacuum filtration, giving a hygroscopic solid.
  • the wet solid was dissolved in a 4:1 (v/v) ethyl acetate-methanol solution (500 ml). The solution was washed with 0.84 M aqueous citric acid (50 ml), dried (MgS0 ), and concentrated in vacuo to a yellow liquid. The liquid was redissolved in fresh ethyl acetate-methanol. The solution was washed with brine, dried (MgS0 4 ), and concentrated in vacuo.
  • a stirring suspension comprised of 7-fluoro-6-(4-iodo-2-methyl- phenylamino)-1H-benzoimidazole-5-carboxylic acid (0.844 g, 2.05x10 "3 mol) in ethyl acetate (4 ml) was added a solution comprised of pentafluorophenol (0.375 g, 2.04x10 "3 mol) in N,N-dimethylformamide (10 ml).
  • Step b Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide
  • Step a Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzoimidazole-5-carboxylic acid 0-(tetrahydro-2H-pyran-2-yl)-oxyamide
  • Step b Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzoimidazole-5-carboxylic acid hydroxyamide
  • Step i Preparation of 2-cylcopropylmethoxy-isoindole-1 ,3-dione
  • Step b Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide
  • Step a Preparation of 5-nitro-2,3,4-trifluorobenzoic acid Same as for Example 1 , Step a.
  • Step b Preparation of 2,3-difluoro-4-hvdroxy-5-nitrobenzoic acid
  • the solid 5-nitro-2,3,4-trifluorobenzoic acid (1.00 g, 0.00452 mol) was dissolved in 10 wt. % aqueous sodium hydroxide solution. The mixture was clear deep orange. After standing under ambient conditions for several minutes, the mixture was quenched with concentrated aqueous hydrochloric acid until strongly acidic (pH 0). A white solid precipitated which was isolated by vacuum filtration and dried with suction to afford 0.40 g of an off-white solid. This solid was recrystallized from chloroform (20 ml) to afford 0.22 g of an off-white crystalline powder; 22 % yield; MS (APCI-) 218 (M-1 , 100).
  • Step c Preparation of methyl 2,3-difluoro-4-hydroxy-5-nitrobenzoate Anhydrous hydrogen chloride gas was dissolved in anhydrous methanol (50 ml) until the solution was warm. The microcrystalline solid 2,3- difluoro-4-hydroxy-5-nitrobenzoic acid 0.22 g, 0.00100 mol) was dissolved in the methanolic hydrogen chloride solution. The stirring reaction mixture was brought to reflux under nitrogen for 16 hours. The mixture was concentrated in vacuo to give a white solid. The product was dried under high vacuum to afford 0.213 g of a white powder; 91 % yield; m.p.
  • Step e Preparation of 1-adamantyl 4-carboxymethyl-2-fluoro-3-(2-methyl- phenylamino)-6-nitrophenyl carbonate
  • the compound 1-adamantyl 4-carboxymethyl-2,3-difluoro-6-nitrophenyl carbonate is dissolved in excess ott ⁇ o-toluidine.
  • the reaction mixture is stirred at 200 °C for 6 hours.
  • the mixture is allowed to cool and is dissolved in diethyl ether.
  • the organic phase is washed with dilute aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, is dried (MgS0 ), and is concentrated in vacuo to afford the desired product.
  • the product is purified by flash chromatography as necessary.
  • Step f Preparation of methyl 3-fluoro-4-hvdroxy-2-(2-methyl-phenylamino)-5- nitrobenzoate
  • Step h Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino)-1 H- benzooxazole-5-carboxylate
  • the compound 5-amino-3-fluoro-4-hydroxy-2-(2-methyl-phenylamino)- benzoate is treated as in Step f, Example 1.
  • the product may be recrystallized with an appropriate solvent like chloroform or ethanol if further purification is necessary.
  • Step i Preparation of methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzooxazole-5-carboxylate
  • a stirring mixture comprised of methyl 7-fluoro-6-(2-methyl- phenylamino)-1 H-benzooxazole-5-carboxylate (0.042 M), benzyltrimethylammonium dichloroiodinate (Aldrich, 95 %, 0.057 M, 1.36 equiv.), and zinc chloride (0.070 M, 1.67 equiv.) in glacial acetic acid is brought to reflux for 15 minutes. The mixture is concentrated in vacuo and the residue taken up into diethyl ether.
  • the ether solution is washed with dilute aqueous hydrochloric acid, water, and brine, is dried (MgS0 ), and is concentrated in vacuo to obtain the desired product.
  • the product may be purified by recrystallization with an appropriate solvent like ethanol.
  • Step j Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzooxazole-5-carboxylic acid
  • Step a Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H- benzooxazole-5-carboxylic acid 0-(tetrahvdro-2H-pyran-2-yl)-oxyamide
  • the compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzooxazole-5-carboxylic acid is treated as in Step a, Example 2.
  • Step b Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzooxazole-5-carboxylic acid hydroxyamide
  • Step a Preparation of 5-nitro-2,3,4-trifluorobenzoic acid Same as for Example 1 , Step a.
  • Step b Preparation of 2,3-difluoro-4-hvdroxy-5-nitrobenzoic acid Same as for Example 4, Step b.
  • Step c Preparation of methyl 2,3-difluoro-4-hydroxy-5-nitrobenzoate Same as for Example 4, Step c.
  • Step d Preparation of 4-dimethylthiocarbamoyloxy-2,3-difluoro-5-nitro- benzoic acid methyl ester
  • a solution of methyl 2,3-difluoro-4-hydroxy-5-nitrobenzoate in N,N- dimethylformamide is treated with one molar equivalent of cesium carbonate and warmed to 85 °C for 30 minutes.
  • the stirring mixture is then treated dropwise rapidly with a solution comprised of a slight excess of N,N- dimethylthiocarbamoyl chloride in N,N-dimethylformamide.
  • the reaction mixture is stirred at room temperature for one hour, or may be warmed over a steam bath for one hour.
  • the mixture is then poured into water and extracted with ethyl acetate.
  • Step e Preparation of 4-Dimethylthiocarbamoyloxy-3-fluoro-5-nitro-2-o- tolylamino-benzoic acid methyl ester
  • the compound 4-dimethylthiocarbamoyloxy-2,3-difluoro-5-nitro-benzoic acid methyl ester is dissolved in excess o-toluidine.
  • the stirring mixture is brought to 200 °C for one hour.
  • the mixture is then poured into 5 % aqueous hydrochloric acid.
  • the aqueous mixture is extracted with diethyl ether.
  • the organic phase is washed with water and brine, is dried over magnesium sulfate, and is concentrated in vacuo.
  • the crude product is purified by ordinary methods such as chromatography or crystallization from an appropriate solvent.
  • Step f Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino)-1 H- benzothiazole-5-carboxylate
  • the compound methyl 5-amino-3-fluoro-4-mercapto-2-(2-methyl- phenylamino)-benzoate is treated as in Step h, Example 4.
  • Step g Preparation of methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzothiazole-5-carboxylate
  • the compound methyl 7-fluoro-6-(2-methyl-phenylamino)-1 H- benzothiazole-5-carboxylate is treated as in Step i, Example 4.
  • Step h Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzothiazole-5-carboxylic acid
  • the compound methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzothiazole-5-carboxylate is treated as in Step j, Example 4.
  • Step a Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H-benzothiazole-5- carboxylic acid hydroxyamide
  • Step a Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzothiazole-5-carboxylic acid 0-(tetrahydro-2H-pyran-2-yl)-oxyamide
  • the compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzothiazole-5-carboxylic acid is treated as in Step a, Example 2.
  • Step b Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzothiazole-5-carboxylic acid hydroxyamide
  • Step a Preparation of 8-fluoro-7-(2-methyl-phenylamino)-guinoxaline-6- carboxylic acid
  • the compound methyl 4,5-diamino-3-fluoro-2-(2-methyl-phenylamino)- benzoate (from Step e, Example 1) is dissolved in 2:1 :1.2 v/v/v of 2.0 M acetic acid-4.0 M sodium acetate-methanol.
  • the suspension is warmed to 65 °C (or until homogeneous) and the clear solution is poured into a 0.078 M aqueous sodium glyoxal bisulfite (Aldrich, monohydrate, 1.05 equiv.) solution which is warmed to 70 °C.
  • the reaction mixture is stirred gently between 55-75 °C for one hour, and is then cooled to 12 °C with an ice-water bath.
  • Pulverized sodium hydroxide pellets (27 equiv.) are added to the cold solution. The mixture is gently warmed to 30 °C and stirred for 45 minutes. The temperature is raised to 70 °C for 15 minutes. The mixture is allowed to cool and is treated with ethyl acetate. The biphasic mixture is treated with concentrated aqueous hydrochloric acid to achieve pH 0 in the aqueous phase. The organic phase is separated, dried (MgS0 4 ), and concentrated in vacuo to give the desired product. The product may be triturated with an appropriate solvent like dichloromethane or recrystallized from a solvent like ethanol for further purification as necessary.
  • Step b Preparation of 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline- 6-carboxylic acid
  • Step a Preparation of 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline-
  • 6-carboxylic acid is treated as in Step a, Example 2.
  • Step b Preparation of 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline-
  • 6-carboxylic acid is treated as in Step b, Example 3.
  • Step a Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino)- benzoH ,2,51thiadiazole-5-carboxylate
  • a stirring solution comprised of methyl 4,5-diamino-3-fluoro-2-(2-methyl- phenylamino)-benzoate (from Step e, Example 1 ) and diisopropylethylamine (2 equiv.) in an appropriate solvent like diethyl ether or toluene is added a reagent like N-thioaniline or thionyl chloride (1.35 equiv.).
  • the reaction mixture is brought to reflux for one hour.
  • the mixture is quenched with dilute aqueous hydrochloric acid.
  • the organic phase is washed with saturated aqueous sodium bicarbonate and brine, is dried (MgS0 ), and is concentrated in vacuo to afford the desired product.
  • the product may be recrystallized with an appropriate solvent like chloroform or ethanol, or may be chromatographed if further purification is necessary.
  • Step b Preparation of methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)- benzofl ,2, 51thiadiazole-5-carboxylate
  • Step c Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)- benzoH ,2,51thiadiazole-5-carboxylic acid
  • Step a Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)- benzofl ,2,51thiadiazole-5-carboxylic acid Q-(tetrahydro-2H-pyran-2-yl)- oxyamide
  • Step b Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)- benzoH ,2,51thiadiazole-5-carboxylic acid hydroxyamide
  • Step a Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino)- benzoFI ,2,51oxadiazole-5-carboxylate 2-oxide See Takakis, I. M.; Hadjimihalakis, P. M., J. Heterocyclic Chem., 27,
  • Step b Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino)- benzo[1 ,2,51oxadiazole-5-carboxylate
  • a solution comprised of methyl 7-fluoro-6-(2-methyl-phenylamino)- benzo[1 ,2,5]oxadiazole-5-carboxylate 2-oxide and sodium azide (1.38 equiv.) in ethylene glycol is heated to 140-150 °C for 30 minutes to obtain, after column chromatography, the desired product.
  • Step c Preparation of methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)- benzof1 ,2,51oxadiazole-5-carboxylate
  • Step d Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)- benzof 1 ,2,51oxadiazole-5-carboxylic acid
  • Step a Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)- benzofl ,2,51oxadiazole-5-carboxylic acid 0-(tetrahvdro-2H-pyran-2-yl)- oxyamide
  • Step b Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)- benzof1.2.5loxadiazole-5-carboxylic acid hydroxyamide
  • Step a Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino)-1 H- benzotriazole-5-carboxylate
  • the compound methyl 4,5-diamino-3-fluoro-2-(2-methyl-phenylamino)- benzoate (from Step e, Example 1) is diazotized by ordinary methods. Workup gives the desired product.
  • Step b Preparation of methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzotriazole-5-carboxylate
  • Step c Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzotriazole-5-carboxylic acid
  • Step a Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H-benzotriazole-5- carboxylic acid hydroxyamide
  • Step a Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzotriazole-5-carboxylic acid Q-(tetrahvdro-2H-pyran-2-yl)-oxyamide
  • the compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzotriazole-5-carboxylic acid is treated as in Step a, Example 2.
  • Step b Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H- benzotriazole-5-carboxylic acid hydroxyamide

Abstract

L'invention concerne une méthode de traitement de la douleur chronique au moyen d'un composé de formule (I).
EP00947013A 1999-07-16 2000-07-05 Methode de traitement de la douleur chronique au moyen d'inhibiteurs de mek Withdrawn EP1202731A2 (fr)

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AU6068600A (en) 2001-02-05
CO5190704A1 (es) 2002-08-29
ZA200109906B (en) 2003-05-28
HUP0202319A2 (en) 2002-10-28
JP2003504398A (ja) 2003-02-04
IL147150A0 (en) 2002-08-14
PE20010546A1 (es) 2001-06-04
KR20020015376A (ko) 2002-02-27
PL352835A1 (en) 2003-09-08
WO2001005390A2 (fr) 2001-01-25
HUP0202319A3 (en) 2004-12-28
WO2001005390A3 (fr) 2001-05-17
CN1358094A (zh) 2002-07-10
CA2377092A1 (fr) 2001-01-25

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