WO2008130322A1 - Nouveaux dérivés 5-hétérocyclyl-chromane utilisés pour le traitement de la douleur - Google Patents

Nouveaux dérivés 5-hétérocyclyl-chromane utilisés pour le traitement de la douleur Download PDF

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Publication number
WO2008130322A1
WO2008130322A1 PCT/SE2008/050461 SE2008050461W WO2008130322A1 WO 2008130322 A1 WO2008130322 A1 WO 2008130322A1 SE 2008050461 W SE2008050461 W SE 2008050461W WO 2008130322 A1 WO2008130322 A1 WO 2008130322A1
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methylpiperazin
chromen
dihydro
phenyl
carboxamide
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PCT/SE2008/050461
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English (en)
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Yevgeni Besidski
Ylva Gravenfors
Inger Kers
Martin Nylöf
Didier Rotticci
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Astrazeneca Ab
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Publication of WO2008130322A1 publication Critical patent/WO2008130322A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to new compounds, to pharmaceutical composition containing said compounds and to the use of said compounds in therapy.
  • the present invention further relates to processes for the preparation of said compounds and to new intermediates useful in the preparation thereof.
  • Voltage-gated sodium channels are critical elements in the control of electrical excitability of various cell types, including muscle and neuronal cells. In muscle and neuronal cells voltage-gated sodium channels are mainly responsible for the rising phase of the action potential. Voltage-gated sodium channels are composed of a single alpha subunit and one or two beta subunits. There are 10 known alpha subunit proteins, of which nine are functional as an ion channel. The different alpha subunit proteins are herein referenced to as Navl.x, with x being an integer between 1 and 9. This labelling is in accordance with the conventions of the International Pharmacological Association (REF).
  • REF International Pharmacological Association
  • Alpha subunits are large proteins of an approximate weight of 260 kDA ( ⁇ 2000 amino acids), and are functional as voltage-gated sodium channels as monomeric structures.
  • Beta subunits are known at present. Beta subunits are smaller proteins of an approximate weight of 33-36 kDa. Beta subunits can modulate functional expression, as well as the characteristics of channel opening and closing (gating) of alpha subunits.
  • voltage-gated sodium channels are important therapeutic targets: a) the biophysical characteristics of voltage-gated sodium channels, b) the tissue expression pattern of voltage-gated sodium channels, c) evidence from preclinical research, d) the association between several congenital diseases and channelopathies of voltage-gated sodium channels, and e) evidence from the usage of pharmacological agents active at voltage-gated sodium channels in the clinic.
  • a main biophysical characteristic of voltage-gated sodium channels is the fast opening and closing (activation and inactivation) of the channel upon an appropriate voltage stimulus.
  • each of these alpha subunits has a characteristic tissue expression pattern. Tissue-specific up- or down-regulation of the expression of several of the voltage-gated sodium channels in human diseases or preclinical disease models in animals strongly supports a central role for specific voltage-gated sodium channels in distinct diseases.
  • Navl.7 is expressed in human neuromas, which are swollen and hypersensitive nerves and nerve endings that are often present in chronic pain states (Acta Neurochirurgica (2002) 144(8) 803-810). Navl.7 is also expressed in dorsal root ganglion neurons and contributes to the small tetrodoxin (TTX) sensitive component seen in these cells. Navl.7 may thus be a potential pain target in addition to its role in neuroendocrine excitability (EMBO Journal (1995) 14(6) 1084-1090).
  • TTX small tetrodoxin
  • the present invention relates to a novel group of compounds that exhibit NaVl.7 inhibiting activity, and are therefore expected to be useful in the prophylaxis and treatment of different acute and chronic pain conditions.
  • WO 97/34883, WO 99/14212, WO 99/05135 and WO 99/14213 describe compounds for use in treatment of pain.
  • the compounds described in these prior art documents bind to serotonine receptors.
  • the compounds of the present invention have little to none activity towards the serotonine receptor.
  • the compounds of the present invention also are contemplated to have an improved pharmacokinetic profile compared to the compounds in the prior art, including a higher oral bioavailability, a decreased clearance and a decreased volume of distribution. Without being bound to any theory, the difference in pharmacokinetic profile is believed to be due to the fact that the right hand side of the molecule is aromatic in the compounds of the present invention while this is not the case for the known compounds.
  • Ri is N or CH;
  • Y is NR 2 CO or NR 2 CONR 2a, wherein R 2 and R 2a are independently H or Ci-C 6 alkyl;
  • R 3 is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be independently mono- or di-substituted with R 4 and/or R 5,
  • R 4 and R 5 are independently selected from H, halogen, CF 3 , OCF 3 , Ci-C 6 alkyl, Ci-C 3 alkoxy, SO 3 CF 3 , phenyl, Ci-C 6 alkyl-phenyl, a non-aromatic 3-5 membered heterocyclic ring containing one or two heteroatoms selected from N, O, and S, said non-aromatic heterocyclic ring optionally being substituted with one or more Ci-C 6 alkyl substituent(s) and a 3-8 membered heteroaromatic ring containing one or two heteroatoms selected from N, O, and S, said heteroaromatic ring optionally being substituted with one or more Ci-C 6 alkyl substituent(s), and n is O, 1 or
  • Ri is N;
  • Y is NR 2 CO or NR 2 CONR 2a , wherein R 2 and R 2a are independently H or Ci-C 4 alkyl;
  • R 3 is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N,
  • R 4 and R 5 are independently selected from H, halogen, CF 3 , C 1 -C 4 alkyl, C 1 -C 3 alkoxy,
  • R 3 is phenyl.
  • R 3 is isoxazolyl.
  • R 3 is pyrazolyl or imidazolyl.
  • R 3 is pyridinyl, thiophenyl, oxazolyl or pyrimidinyl.
  • R 3 is substituted with R 4 and R 5 which are independently selected from halogen, CF 3 , C 1 - C 4 alkyl, Ci-C 3 alkoxy, SO 3 CF 3 , phenyl and Ci-C 3 alkyl-phenyl.
  • R 4 and R 5 are independently selected from a non-aromatic 5-membered heterocyclic ring containing one or two heteroatoms selected from N, O, and S, and a 5-6 membered heteroaromatic ring containing one or two heteroatoms selected from N, O, and S.
  • R 4 is pyrazolyl, furanyl or pyrrolidinyl, which may be substituted with one or more Ci-C 4 alkyl substituent(s).
  • Ri is N or CH;
  • Y is NHCO, NHCONCH 3 , or NHCONCH(CH 3 ) 2 ;
  • R 3 is phenyl, phenyl-Ci-C 3 alkyl, isoxazolyl, pyrazolyl, oxazolyl, imidazolyl, pyridinyl, thiophenyl, or pyrimidinyl;
  • R 4 and R 5 which are independently selected from H, chloro, CH 3 , CH 2 CH 3 , CH 2 CH 2 (CH 3 ) 2 , C(CH 3 ) 3 , (CH 2 ) 3 CH 3 , SO 3 CF 3 , CF 3 , OCH 3 , OCH(CH 3 ) 2 , phenyl, CH 3 - phenyl, pyrazolyl, furanyl and pyrrolidinyl, said pyrazolyl, furanyl, or pyrrolidinyl, said pyrazolyl, furanyl
  • R3 is phenyl, isoxazolyl, pyrazolyl, oxazolyl, imidazolyl, pyridinyl, thiophenyl or pyrimidinyl; R 4 and R 5 which are independently selected from H, chloro, CH 3 , CH 2 CH 2 (CH 3 )2, C(CH 3 ) 3 , (CH 2 ) 3 CH 3 , SO 3 CF 3 , CF 3 , OCH 3 , OCH(CH 3 ) 2 , phenyl, CH 3 -phenyl, pyrazolyl, furanyl and pyrrolidinyl.
  • Ri is N or CH
  • Y is NR 2 CO OrNR 2 CONR 2 , wherein R 2 is H or Ci-C 6 alkyl;
  • R 3 is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N,
  • R 4 is H, CF 3 , OCF 3 , Ci-C 6 alkyl, Ci-C 3 alkoxy, SO 3 CF 3 , phenyl, phenyl-Ci-C 6 alkyl, a non-aromatic 3-5 membered heterocyclic ring containing one or two heteroatoms selected from N, O, and S, said non-aromatic heterocyclic ring optionally being substituted with one or more Ci-C 6 alkyl substituent(s), a 3-8 membered heteroaromatic ring containing one or two heteroatoms selected from N, O, and S, said heteroaromatic ring optionally being substituted with one or more Ci-C 6 alkyl substituent(s),
  • alkyl includes both straight and branched chain alkyl groups and may be, but are not limited to methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl or i-hexyl.
  • the term having 1 to 4 carbon atoms and may be but are not limited to methyl, ethyl, n-propyl, i-propyl or t-butyl.
  • Co in Co-4 alkyl refers to a situation where no carbon atom is present.
  • alkoxy refers to radicals of the general formula -O-R, wherein R is selected from a hydrocarbon radical.
  • alkoxy may include, but is not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy or isobutoxy.
  • amine or “amino” refers to radicals of the general formula -NRR', wherein R and R' are independently selected from hydrogen or a hydrocarbyl radical.
  • aromatic refers to hydrocarbyl radicals having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n + 2 delocalized electrons) and comprising 6 up to about 14 carbon atoms.
  • aryl used alone or as suffix or prefix, refers to a hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms, wherein the radical is located on a carbon of the aromatic ring.
  • aromatic character e.g., 4n + 2 delocalized electrons
  • 'alkylphenyl' refers to a phenyl group which is mono-, di-, or tri-substituted with alkyl such as for example methylphenyl in example 4.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine radicals.
  • heterocycle or “heterocyclic” or “heterocyclic ring” refers to ring-containing monovalent and divalent radicals having one or more heteroatoms, independently selected from N, O, P and S, as part of the ring structure and comprising at least 3 and up to about 20 atoms in the rings preferably 5 and 6 membered rings. Heterocyclic ring may be saturated or unsaturated and contain one or more double bonds.
  • heterocyclic monovalent and divalent radicals having aromatic character may be, but is not limited to oxazolyl, isoxazol, furyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl, indazolyl, pyridonyl or benzothienyl.
  • Heteroaryl may also be quinolinyl, quinoxalinyl, naphthyridinyl, isoquinolinyl or thiazolyl.
  • hydrocarbyl refers to any structure comprising only carbon and hydrogen atoms up to 14 carbon atoms.
  • a group R 3 substituted with a group SO 3 CF 3 is an R 3 substituted with trifiuoromenthanesulfonic acid.
  • mammal includes any of various warm-blooded vertebrate animals of the class Mammalia, including but not limited to humans, generally characterized by a covering of hair on the skin.
  • Another embodiment of the invention relates to compounds selected from the group consisting of
  • the present invention relates to any one of the specific compounds mentioned above.
  • the present invention relates to the compounds of formula I or Ia as hereinbefore defined as well as to pharmaceutical acceptable salts thereof.
  • Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I or Ia.
  • a suitable pharmaceutically acceptable salt of the compounds of the invention is, for example, an acid-addition salt, for example a salt with an inorganic or organic acid.
  • a suitable pharmaceutically acceptable salt of the compounds of the invention is an alkali metal salt, an alkaline earth metal salt or a salt with an organic base.
  • Other pharmaceutically acceptable salts and methods of preparing these salts may be found in, for example, Remington's Pharmaceutical Sciences (18th Edition, Mack Publishing Co.).
  • the compounds of the present invention may also exists as solvents, solvated hydrates or cocrystals.
  • the compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.
  • the compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric esters by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.
  • Another object of the invention relates to processes (a) or (b) for the preparation of compounds of general Formula I and Ia and salts thereof.
  • the transformation may be performed using a suitable activating reagent such as 2-(1H- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate or N,N'- carbonyldiimidazole with a suitable base such as triethylamine or diisopropylethylamine.
  • a suitable activating reagent such as 2-(1H- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate or N,N'- carbonyldiimidazole with a suitable base such as triethylamine or diisopropylethylamine.
  • the reaction may be performed in a suitable solvent such as dimethylformamide, acetonitrile or dichloromethane at a temperature between -20 0 C and reflux.
  • the reaction may be preformed in a suitable solvent such as dichloromethane or dimethylformaide at a temperature between -20 °C and reflux.
  • a suitable solvent such as dichloromethane or dimethylformaide
  • Protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore.
  • the compounds of the invention exhibit voltage-gated sodium channel inhibiting activity, especially Navl .7 blocking activity, for example as demonstrated in the test described below.
  • the present invention relates to the compounds of formula I or Ia, which inhibit any sodium channel. Modulation of voltage-gated sodium channels by pharmacological or genetical tools points to a central role for distinct voltage-gated sodium channels in several disease models.
  • a mouse line has been generated which through advanced molecular biology technologies eliminates the functional expression of Navl.7 in DRG neurons that express Navl.8 (Proceedings of the National Academy of Sciences USA (2004) 101(34) 12706-12711). This mouse line shows greatly reduced pain responses in several pain behaviour models. Likewise, Herpes-vector mediated knockdown of Navl .7 in primary afferents of wildtype mice results in a decrease in inflammatory hyperalgesia (Human Gene Therapy (2005) 16(2) 271-277).
  • Antagonists of NaV channels have been shown to be useful for treating a variety of conditions, including acute and chronic nociceptive, visceral, inflammatory, central and peripheral neuropathic pain. More specifically, modulators of NaV activity are currently used or being tested in the clinic as anaesthetics, including local anaesthetics (Pain (2000) 87(1) 7-17), neuropathic pain reliefers (European Journal of Pain (2002) 6(Supplement 1) 61-68), acute pain reliefers (The Cochrane Database of Systematic Reviews (2005) 3), chronic pain reliefers (Pharmacotherapy (2001) 21(9) 1070-1081), inflammatory pain reliefers (Proceedings of the National Academy of Sciences USA (1999) 96(14) 7645- 7649), headache reliefers (Headache (2001) 41(Supplement 1) S25-S32).
  • the compounds of the invention are thus expected to be useful in both the prophylaxis and the treatment of a condition which is effected or facilitated by inhibition of voltage-gated sodium channels, in particular pain, such as acute and chronic pain disorders including but not limited to widespread pain, localized pain, nociceptive pain, inflammatory pain, central pain, central and peripheral neuropathic pain, central and peripheral neurogenic pain, central and peripheral neuralgia, low back pain, postoperative pain, visceral pain, pelvic pain, allodynia, anesthesia dolorosa, causalgia, dysesthesia, fibromyalgia, hyperalgesia, hyperesthesia, hyperpathia, ischemic pain, sciatic pain, pain associated with cystitis, including but not limited to interstitial cystitis, pain associated with multiple sclerosis, pain associated with arthritis, pain associated with osteoarthritis, pain associated with rheumatoid arthritis and pain associated with cancer.
  • pain such as acute and chronic pain disorders including but not limited to widespread pain, localized pain,
  • the compounds of the present invention may be administered alone or in combination with other compounds, especially therapeutically active compounds.
  • the compounds of the present invention may for example be combined with one or more of the following therapeutically active compounds: proton pump inhibitors such as omeprazole, lansoprazole, rabeprazole, tentorpazole, pantoprazole, esomeprazole, revaprazan or sorprazan.
  • proton pump inhibitors such as omeprazole, lansoprazole, rabeprazole, tentorpazole, pantoprazole, esomeprazole, revaprazan or sorprazan.
  • one embodiment of the invention relates to a combination wherein a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester, solvates, hydrated solvates, hydrates or co crystals thereof, or a pharmaceutical composition or formulation comprising a compound of formula (I) or (Ia) is administered concurrently, simultaneously, sequentially or separately with another pharmaceutically active compound or compounds selected from the following: (i) antidepressants such as agomelatine, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, pro trip ty line, ramelteon, rebox
  • anxiolytics including for example alnespirone, azapirones,benzodiazepines, barbiturates such as adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, zolazepam and equivalents and pharmaceutically active
  • Alzheimer's therapies including for example donepezil, memantine, tacrine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof
  • Parkinson's therapies including for example deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • migraine therapies including for example almotriptan, amantadine, bromocriptine, butalbital, cabergoline, dichloralphenazone, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pramipexole, rizatriptan, ropinirole, sumatriptan, zolmitriptan, zomitriptan, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • (ix) stroke therapies including for example abciximab, activase, NXY-059, citicoline, crobenetine, desmoteplase,repinotan, traxoprodil and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • urinary incontinence therapies including for example darafenacin, falvoxate, oxybutynin, propiverine, robalzotan, solifenacin, tolterodine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • neuropathic pain therapies including for example gabapentin, lidoderm, pregablin and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • nociceptive pain therapies such as celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, paracetamol and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • GABAb modulators such as baclofen, and equivalents and pharmaceutically active salts and metabolite(s) thereof.
  • insomnia therapies including for example agomelatine, allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol, etomidate, glutethimide, halazepam, hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital, phenobarbital, propofol, ramelteon, roletamide, triclofos,secobarbital, zaleplon, Zolpidem and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • mood stabilizers including for example carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, verapamil, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • Such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active compound or compounds within therapeutically active dosage ranges and/or the dosage described in the publication reference.
  • One embodiment of the invention relates to compounds of formula I or Ia as defined above, or any of the specific compounds mentioned above, or pharmaceutically acceptable salts thereof, or any of the specific salts mentions for these compounds, for use in therapy.
  • Another embodiment relates to the use of compounds of formula I or Ia as defined above, or any of the specific compounds mentioned above, or pharmaceutically acceptable salts thereof, or any of the specific salts mentions for these compounds, in the manufacture of a medicament for treatment of pain.
  • a further embodiment relates to the use of compounds of formula I or Ia as defined above, or any of the specific compounds mentioned above, or pharmaceutically acceptable salts thereof, or any of the specific salts mentions for these compounds, in the manufacture of a medicament for treatment of acute or chronic nociceptive pain, visceral pain, inflammatory pain, and/or central or peripheral neuropathic pain.
  • One embodiment relates to a method of treatment of pain, or acute or chronic nociceptive pain, visceral pain, inflammatory pain, and/or central or peripheral neuropathic pain in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compounds of formula I or Ia as defined above, or any of the specific compounds mentioned above, or pharmaceutically acceptable salts thereof, or any of the specific salts mentions for these compounds, or a pharmaceutical composition comprising said compounds.
  • An agent for the treatment of pain, or acute or chronic nociceptive pain, visceral pain, inflammatory pain, and/or central or peripheral neuropathic pain which comprises as active ingredient a compounds of formula I or Ia as defined above , or any of the specific compounds mentioned above, or pharmaceutically acceptable salts thereof, or any of the specific salts mentions for these compounds, or a pharmaceutical composition comprising said compounds.
  • compositions will normally be administered orally, subcutaneously, intravenously, intraarterially, transdermally, intranasally, by inhalation, or by any other parenteral route, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or a non-toxic organic or inorganic acid addition salt, in a pharmaceutically acceptable dosage form.
  • the compositions may be administered at varying doses.
  • One embodiment relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound of formula I or Ia as defined above, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.
  • Another embodiment relates to said pharmaceutical composition according, for use in the treatment of pain or acute or chronic nociceptive pain, visceral pain, inflammatory pain, and/or central or peripheral neuropathic pain.
  • Suitable daily doses of the compounds of the invention in therapeutic treatment of humans are about 0.005 to 25.0 mg/kg body weight at oral administration and about 0.005 to 10.0 mg/kg body weight at parenteral administration.
  • Example of ranges of daily doses of the compounds of the invention in therapeutic treatment of humans are about 0.005 to 10.0 mg/kg body weight at oral administration and about 0.005 to 5.0 mg/kg body weight at parenteral administration.
  • Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, be longer acting than, produce fewer side effects than, be more easily absorbed than, or that they may have other useful pharmacological properties over, compounds known in the prior art.
  • Microwave irradiation was performed in a Creator , Initiator or Smith Synthesizer Single -mode microwave cavity producing continuous irradiation at 2450 MHz. Mass spectra were recorded on one of the following instruments: a Perkin-Elmer SciX API 150ex spectrometer; a VG Quattro II triple quadrupole; a VG Platform II single quadrupole; or a Micromass Platform LCZ single quadrupole mass spectrometer (the latter three instruments were equipped with a pneumatically assisted electrospray interface (LC- MS)).
  • LC- MS pneumatically assisted electrospray interface
  • Prep-HPLC Preparative chromatography was run on Waters auto purification HPLC with a diode array detector. Column: XTerra MS C8, 19 x 300 mm, 10 ⁇ m. Gradient with acetonitrile/0.1 M ammonium acetate in 5 % acetonitrile in MiIIiQ Water, typically run from 20% to 60% acetonitrile, in 13 min. Flow rate: 20 mL/min. Alternatively, purification was achieved on a semi preparative Shimadzu LC-8A HPLC with a Shimadzu SPD-IOA UV- vis. -detector equipped with a Waters Symmetry ® column (C 18, 5 ⁇ m, 100 mm x 19 mm).
  • NMR spectra were recorded on a Varian Unity+ 400 NMR Spectrometer, operating at 400 MHz for proton and 100 MHz for carbon- 13, and equipped with a 5 mm BBO probe with Z-gradients; or on a Bruker av400 NMR spectrometer operating at 400 MHz for proton and 100 MHz for carbon-13, and equipped with a 3 mm flow injection SEI 1 HZD- 13 C probehead with Z-gradients, using a BEST 215 liquid handler for sample injection; or on a Bruker DPX400 NMR spectrometer, operating at 400 MHz for proton and 100 MHz for carbon-13, and equipped with a 4-nucleus probe with Z-gradients.
  • TMS ⁇ 0.00 or the residual solvent signal of OMSO-d ⁇ ⁇ 2.49, CD 3 OD ⁇ 3.31 or CDCl 3 ⁇ 7.25 (unless otherwise indicated).
  • Resonance multiplicities are denoted s, d, t, q, m and br for singlet, doublet, triplet, quartet, multiplet and broad, respectively.
  • Column chromatography was performed using Merck Silica gel 60 (0.040-0.063 mm), or employing a Combi Flash ® Companion TM system using RediSep TM normal-phase flash columns.
  • Rotamers may or may not be denoted in spectra depending upon ease of interpretation of spectra. Unless otherwise stated, chemical shifts are given in ppm with the solvent as internal standard.
  • Acid 3 5-methyl-l -phenyl- lH-pyrazole-4-carboxylic acid
  • Acid 4 biphenyl-3 -carboxylic acid
  • Acid 7 5-(l-ethyl-5-methyl-lH-pyrazol-4-yl)isoxazole-3-carboxylic acid
  • Acid 9 5 -isobutylisoxazole-3 -carboxylic acid
  • Acid 10 5-methyl-l-(2-methylphenyl)-lH-pyrazole-4-carboxylic acid
  • Acid 15 5-methyl-2-phenyl-l,3-oxazole-4-carboxylic acid
  • Acid 17 2-phenyl-lH-imidazole-4-carboxylic acid
  • Acid 19 5 -tert-butyl-1 -phenyl- lH-pyrazole-3-carboxylic acid
  • Acid 22 5-butylpyridine-2-carboxylic acid
  • Acid 24 4-tert-butylbenzoic acid
  • Acid 26 2-chloro-4-pyrrolidin-l-ylbenzoic acid
  • Acid 27 4- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ benzoic acid
  • Acid 28 4-isopropoxybenzoic acid
  • Acid 33 6-phenyl-4-pyrimidinecarboxylic acid
  • Secondary amines 2-phenyl-lH-imidazole-4-carboxylic acid
  • Acid 19 5 -tert-butyl-1 -phenyl- lH-pyrazole-3-carboxylic acid
  • Acid 22 5-butylpyridine-2-carboxylic acid
  • Acid 24 4-tert-but
  • Method B 7V,7V'-Carbonyldiimidazole (1.2 mole equivalent) was added to a solution of the carboxylic acid (1.2 mole equivalent) in anhydrous dimethylformamide followed by addition of a solution of the amine (1 mole equivalent) in anhydrous dimethylformamide.
  • the reaction mixture was heated at 80 0 C for 2-12 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated in vacuo to yield the crude product. Purification by preparative HPLC. Method C:
  • Triethylamine (3 mole equivalent) and 2-(lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafiuorophosphate (1.5 mole equivalent) were added to a solution of the carboxylic acid (1 mole equivalent) in anhydrous acetonitrile and he reaction mixture was stirred for 10 min.
  • a solution of the amine (1 mole equivalent) in anhydrous acetonitrile was added and the reaction mixture was stirred at ambient temperature for 1 h. The volatiles were removed in vacuo and the crude residue was purified by preparative HPLC.
  • Method D The secondary amine (as the hydrochloride, 1 mole equivalent) was added to a solution of 7V,7V'-carbonyldiimidazole in anhydrous dichloromethane and the mixture was stirred at ambient temperature for 40 min. The amine (1 mole equivalent) and triethylamine (1 mole equivalent) were added and the reaction mixture was stirred at ambient temperature overnight. The volatiles were removed in vacuo and the crude product was purified by preparative HPLC.
  • Trimethylaluminium (2 M in hexanes, 0.11 mL, 0.22 mmol) was added to a solution of (35)-5-(4-methylpiperazin-l-yl)chroman-3 -amine (55 mg, 0.22 mmol) in dichloromethane (1.5 mL).
  • the solution was stirred at ambient temperature under an atmosphere of nitrogen for 15 min, and was then added dropwise to a solution of methyl 4-phenylpyridine-2- carboxylate (39 mg, 0.18 mmol) in dichloromethane (1.5 mL).
  • the reaction mixture was stirred at ambient temperature under an atmosphere of nitrogen for 7 h.
  • Gene(s) encoding the full-length protein of the voltage-gated sodium channel of interest are cloned and expressed under a suitable promoter in a suitable cell line, as well known in the art.
  • the so constructed stable cell lines are used in screening assays to identify suitable compounds active on voltage-gated sodium channels. Suitable screening assays are as follows.
  • Li + influx assay The cell line expressing the voltage-gated sodium channel of interest is plated in conventional 96 or 384 well tissue plates at a suitable cell density (for example 40000 cells/well in 96 well plate, or 20000 cells/well in 384 well plate). The cells are then repeatedly washed with a suitable Na free buffer using a suitable commercially available washer (for example EL-405 washer) until all tissue culture medium is removed from the wells.
  • a suitable Na-free buffer could have the composition (mM) Choline chloride 137, KCl 5.4, MgSO 4 0.81, CaCl 2 0.95, glucose 5.55 and HEPES 25 at pH 7.4, but may also have other suitable composition. After completion of all wash steps, cells are incubated in the suitable Na free buffer for 15 min.
  • a buffer rich in LiCl for 60 min at 37 0 C.
  • the LiCl buffer is also enriched in potassium ions, causing a depolarizing stimulus to the cells.
  • Such a buffer may have the composition (mM): LiCl 100, KCl 50, MgSO 4 0.81, CaCl 2 0.95, glucose 5.55 and HEPES 25 at pH 7.4, but may also have other suitable composition.
  • an effective concentration for example 100 ⁇ M
  • the voltage-gated sodium channel opener veratridine, or any other suitable voltage-gated sodium channel opener may be added to the medium to enhance signal detection.
  • an effective concentration for example 10 ⁇ g/ml
  • suitable scorpion venom may also be added to the medium to delay channel inactivation.
  • the assay can be complemented with compounds from a compound library. Compounds of interest are added to the Li-rich solution, one in each well. At the end of the incubation period cells are repeatedly washed with Na free buffer until all extracellular LiCl is removed. Cell lysis is obtained through incubation of cells with triton (1%) for 15 min, or any other suitable method. The resulting cell lysate is then introduced into an atomic absorption spectrophotometer, thus quantifying the amount of Li-influx during the procedure described above.
  • the described assay can be run with any atomic absorption spectrophotometer using plates of 96-well format, 384-well format, or any other conventional plate format.
  • the described assay can be applied to cell lines expressing any given one or more of the voltage-gated sodium channel alpha subunits, as well as any given combination of one of the voltage- gated alpha subunits with any one or more beta subunit.
  • the cell line of choice can be further hyperpolarised by expression of a suitable potassium leak ion channel, for example TREK-I, either by transient co-transfection or through establishment of a stable co-transfected cell line.
  • a suitable potassium leak ion channel for example TREK-I
  • the successful expression of a leak K current can be verified using traditional intracellular electrophysiology, either in whole cell patch-clamp, perforated patch-clamp or conventional two-electrode voltage- clamp.
  • a cell line of choice modified to successfully express a voltage-gated sodium channel of interest together with a suitable potassium leak ion channel transfected can then be used for screening using atomic absorptions spectrometry, as described above.
  • Electrophysiological recordings of sodium currents in cells stably expressing the voltage- gated sodium channel of interest confirms activity and provides a functional measure of the potency of compounds that specifically inhibit such channels.
  • Electrophysiological studies can be performed using automated patch-clamp electrophysiology platforms, like IonWorks HT, Ion Works Quattro, PatchXpress, QPatch or any other suitable platform.
  • the cell line expressing the voltage-gated sodium channel of interest is appropriately prepared as suggested by the manufacturer of the automated patch-clamp platforms. Suitable extracellular and intracellular buffer for such experiments are applied according to the instructions given by the manufacturer of the automated patch- clamp platforms.
  • Cells that express the voltage-gated sodium channel protein of interest are exposed to drugs through the pipetting system integrated in the platforms.
  • a suitable voltage stimulus protocol is used to activate the voltage-gated sodium channel proteins of interest through depolarisation from a defined holding potential.
  • Electrophysiological studies can also be performed using the whole cell configuration of the standard patch clamp technique.
  • cells that express the voltage-gated sodium channel protein of interest are exposed to the drugs by conventional microperfusion systems and a suitable voltage stimulus protocol is used to activate the voltage-gated sodium channels.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés et les sels pharmaceutiquement acceptables de ces derniers ainsi que de nouveaux intermédiaires utilisés dans la préparation de ces composés, des compositions pharmaceutiques contenant ces composés et l'utilisation de ces mêmes composés en thérapie.
PCT/SE2008/050461 2007-04-23 2008-04-22 Nouveaux dérivés 5-hétérocyclyl-chromane utilisés pour le traitement de la douleur WO2008130322A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8227468B2 (en) 2010-10-19 2012-07-24 Eli Lilly And Company Cathepsin S inhibitor compounds
WO2016007043A1 (fr) * 2014-07-08 2016-01-14 Общество с ограниченной ответственностью "Леофорс" Dérivés de 2н-chromène en tant qu'analgésiques
WO2020054657A1 (fr) 2018-09-10 2020-03-19 科研製薬株式会社 Dérivé d'amide hétéroaromatique et médicament le contenant

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997034883A1 (fr) * 1996-03-22 1997-09-25 Astra Aktiebolag Derives de 1,2,3,4-tetrahydronaphthalene substitues
WO1999005134A1 (fr) * 1997-07-25 1999-02-04 Astra Aktiebolag Derives de 1,2,3,4-tetrahydronaphthalene substitue
WO1999014213A1 (fr) * 1997-09-18 1999-03-25 Astrazeneca Ab Derives de chromane substitue
WO1999014212A1 (fr) * 1997-09-18 1999-03-25 Astrazeneca Ab Derives de chromane substitues
WO2005013914A2 (fr) * 2003-08-08 2005-02-17 Vertex Pharmaceuticals Incorporated Compositions utilisees comme inhibiteurs de canaux sodium voltage dependants
US20060025415A1 (en) * 2003-08-08 2006-02-02 Gonzalez Jesus E Iii Compositions useful as inhibitors of voltage-gated sodium channels

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997034883A1 (fr) * 1996-03-22 1997-09-25 Astra Aktiebolag Derives de 1,2,3,4-tetrahydronaphthalene substitues
WO1999005134A1 (fr) * 1997-07-25 1999-02-04 Astra Aktiebolag Derives de 1,2,3,4-tetrahydronaphthalene substitue
WO1999014213A1 (fr) * 1997-09-18 1999-03-25 Astrazeneca Ab Derives de chromane substitue
WO1999014212A1 (fr) * 1997-09-18 1999-03-25 Astrazeneca Ab Derives de chromane substitues
WO2005013914A2 (fr) * 2003-08-08 2005-02-17 Vertex Pharmaceuticals Incorporated Compositions utilisees comme inhibiteurs de canaux sodium voltage dependants
US20050137190A1 (en) * 2003-08-08 2005-06-23 Gonzalez Jesus E.Iii Compositions useful as inhibitors of voltage-gated sodium channels
US20060025415A1 (en) * 2003-08-08 2006-02-02 Gonzalez Jesus E Iii Compositions useful as inhibitors of voltage-gated sodium channels

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8227468B2 (en) 2010-10-19 2012-07-24 Eli Lilly And Company Cathepsin S inhibitor compounds
WO2016007043A1 (fr) * 2014-07-08 2016-01-14 Общество с ограниченной ответственностью "Леофорс" Dérivés de 2н-chromène en tant qu'analgésiques
US9999613B2 (en) * 2014-07-08 2018-06-19 Obshestvo S Ogranichennoi Otvetsvennostju “Leofors” 2H-chromene derivatives as analgesic agents
EA032413B1 (ru) * 2014-07-08 2019-05-31 Общество С Ограниченной Ответственностью "Леофорс" (Ооо "Леофорс") Производные 2н-хромена в качестве анальгезирующих средств
WO2020054657A1 (fr) 2018-09-10 2020-03-19 科研製薬株式会社 Dérivé d'amide hétéroaromatique et médicament le contenant
KR20210057008A (ko) 2018-09-10 2021-05-20 가껭세이야꾸가부시기가이샤 신규한 헤테로방향족 아미드 유도체 및 이를 함유하는 약제

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