WO2009005460A1 - Inhibiteurs à petites molécules de canaux sodiques navl.7 pour le traitement de douleurs - Google Patents

Inhibiteurs à petites molécules de canaux sodiques navl.7 pour le traitement de douleurs Download PDF

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WO2009005460A1
WO2009005460A1 PCT/SE2008/050789 SE2008050789W WO2009005460A1 WO 2009005460 A1 WO2009005460 A1 WO 2009005460A1 SE 2008050789 W SE2008050789 W SE 2008050789W WO 2009005460 A1 WO2009005460 A1 WO 2009005460A1
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phenyl
methoxy
ethanol
butyl
methyl
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PCT/SE2008/050789
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English (en)
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Yevgeni Besidski
Alf Claesson
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Astrazeneca Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • 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
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to new compounds, to a pharmaceutical composition containing said compounds and to the use of said compounds in therapy.
  • the present invention also relates to processes for the preparation of said compounds.
  • the current treatment regimes for pain conditions utilise compounds which exploit a very limited range of pharmacological mechanisms.
  • One class of compounds, the opioids stimulates the endogenous endorphine system; an example from this class is morphine.
  • Compounds of the opioid class have several drawbacks that limit their use, e.g. emetic and constipatory effects and negative influence on respiratory capability.
  • the second major class of analgesics, the non-steroidal antiinflammatory analgesics of the COX-I or COX-2 types also have liabilities such as insufficient efficacy in severe pain conditions and at long term use the COX-I inhibitors cause ulcers of the mucosa.
  • Mechansims of analgesic effects of other currently used medicines are insufficiently characterized and/or have limited therapeutic potential.
  • Local anesthetics that are known to block most types of sodium channels in nerves, are useful for relieving pain in small areas of the human body and for blocking nerve conduction from the periphery to the central nervous system. They can also be used in the last-mentioned way to block sensory signalling by instilling solutions of local anesthetics at the spinal cord. Due to their high toxicity, in particular heart toxicity, they can not, however, be used for systemic administration as generally useful analgesics. There remains thus a need for more selective modulators of sodium channels involved in pain signal conduction.
  • neuropathic pain include, but are not limited to, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias.
  • ectopic activity in the injured nerve corresponds to the behavioral signs of pain.
  • intravenous application of the sodium channel blocker and local anesthetic lidocaine can suppress the ectopic activity and reverse the tactile allodynia at concentrations that do not affect general behavior and motor function (Mao J and Chen LL, Pain, 2000, 87, 7-17).
  • sodium channel blockers In addition to neuropathic pain, sodium channel blockers have clinical uses in the treatment of epilepsy and cardiac arrhythmias. Recent evidence from animal models suggests that sodium channel blockers may also be useful for neuroprotection under ischaemic conditions caused by stroke or neural trauma and in patients with multiple sclerosis (MS).
  • MS multiple sclerosis
  • 2-amino-l,l-diphenyl-ethanols are known from the literature and have been reported to exert many pharmacological actions. Examples of l-(5-alkyl-2-methoxy-phenyl)-l- heteroaryl-2-dialkylamino-ethanols have not been described in the literature (Pharmacology 1994, 49, 238-48).
  • A is a monocyclic or bicyclic heteroaryl containing from 5 to 13 ring atoms, or phenyl, wherein said heteroaryl is optionally substituted with one or more groups R and wherein said phenyl is 4-substituted with a 5-membered heterocycle such as thiazolyl or imidazolyl;
  • R 5 is selected from halo; -NO 2 ; -CN; -OCF 3 ; CF 3 ; Ci -6 fluoroalkoxy; Ci -3 alkoxymethyl; -Ci. 6 haloalkyl; aryl optionally substituted with halo; heteroaryl; carbamoyl; sulphamoyl; C 1-4 alkyl; C2-4alkenyl; C2-6alkynyl; Ci_6alkoxy; Ci- ⁇ alkoxyalkyl; TV-(C i.6alkyl)animo; ⁇ /, ⁇ /-(Ci.6alkyl)2carbamoyl;
  • Ci -6 alkyl N-(Ci -6 alkyl)icarbamoyl; Ci -6 alkylS(O) a wherein a is 0 to 2; Ci -6 alkylSO 2 O;
  • R 1 and R 2 may together with N form a 3-6 membered heterocyclyl ring;
  • R 1 and R 2 may together with N form a 5-6- membered heteroaryl which may optionally be substituted with Ci-C 4 alkyl;
  • X is selected from O, S, SO, SO 2 , and a bond
  • R 3 is selected from C 1-4 alkyl, C2-4alkynyl, and C ⁇ .scarbocyclyl; or
  • R 3 is selected from halo, C 1-6 alkyl, C 2 - 4 alkynyl, and C3-5carbocyclyl;
  • R 4 is selected from C 1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C 5 -i 2 aralkyl, C 5 -i 2 heteroaryloxy, -C 2 - 6 alkylsulfanyl, -C 2 - 6 alkoxy, Ci -4 alkoxyCi -4 alkyl, -C 2 - 6 alkylsulfonyl, and -C 2 - 6 alkylsulfinyl, and is optionally substituted with one or more fiuoro;
  • One embodiment of the invention is related to compounds of formula I, wherein
  • A is a monocyclic or bicyclic heteroaryl having from 1 to 4 hetero ring atoms selected from N, S, and O.
  • One embodiment of the invention is related to compounds of formula I, wherein A is a monocyclic heteroaryl selected from furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and tetrazolyl. .
  • Yet an embodiment of the invention is related to compounds of formula I, wherein A is selected from: thiazol; thiazole substituted by methyl; thiazole substituted by p- fluorophenyl; pyridine di-substituted by methyl and by -CH 2 -O-CH 3 ; pyridine substituted by -OCH2CHF2; pyridine di-substituted by methyl and by CF 3 .
  • Still an embodiment of the invention is related to compounds of formula I, wherein A is phenyl.
  • Yet an embodiment of the invention is related to compounds of formula I, wherein A is phenyl substituted by thiazole; or phenyl substituted by imidazole.
  • A is a bicyclic heteroaryl selected from benzimidazolyl, benzpyrazolyl, benzoxazolyl, imidazopyridinyl, imidazopyrazinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, isoquinolinyl, quinolinyl, quinazolinyl, quinoxalinyl, benzothiazolyl, benzofuranyl, benzodiazepinyl, pyrrolopyridyl, furopyridyl, indolyl, and isoindolyl.
  • Yet an embodiment of the invention is related to compounds of formula I, wherein A is selected from: benzothiazole substituted by fiuoro; quinoline; and quinoxaline.
  • R 1 and R 2 is each and independently selected from H; methyl; ethyl; propyl; i-propyl; butyl; cyclobutyl; -CH 2 -CH-(CH 3 ) 2 ; propanol; -CH 2 -(cyclopropyl);
  • Still an embodiment of the invention is related to compounds of formula I, wherein R 1 and R 2 together with N form a 3-6 membered heterocyclyl ring Still an embodiment of the invention is related to compounds of formula I, wherein R 1 and R 2 together with N form an imidazolyl ring.
  • Still an embodiment of the invention is related to compounds of formula I, wherein R 1 and R 2 together with N form an imidazol ring substituted by a methyl group.
  • Still an embodiment of the invention is related to compounds of formula I, wherein R 1 and R 2 together with N form a pyrrolidinyl ring.
  • One embodiment of the invention is related to compounds of formula I, wherein X is selected from O, S, and a bond.
  • X is O.
  • Still an embodiment of the invention is related to compounds of formula I, wherein R 3 is methyl.
  • Still an embodiment of the invention is related to compounds of formula I, wherein X is a bond and R 3 is Cl or Br.
  • R 4 is selected from Ci_6alkyl, Ci -6 fluoroalkyl; Ci -6 fluoroalkoxy; C2-6alkenyl, and C2-6alkynyl, optionally substituted with one or more fluoro.
  • Still an embodiment of the invention is related to compounds of formula I, wherein R 4 is selected from -CH 2 -CH 2 -C-(CH 3 ) 2 -F; -CH 2 -C-(CH 3 ) 2 -F; -0-CH 2 -CF 3 ; -0-CH 2 -CHF 2 ; and i-butyl.
  • Still an embodiment of the invention is related to compounds of formula I, wherein R 4 is bonded to the phenyl ring in para-position in relation to to the group R 3 -X-. Still an embodiment of the invention is related to compounds of formula I, wherein R 5 is selected from halo, CF 3 ; -OCF 3 , -OCHF 2 , -d-efluoroalkyl, C 1-4 alkyl, C2-4alkenyl, C2-6alkynyl, and Ci_6alkoxy.
  • Still an embodiment of the invention is related to compounds of formula I, wherein R 5 is selected from halo; CF 3 ; -OCHF 2 ; -0-CH 2 -CHF 2 ; CH 2 -OCH 3 ;phenyl substituted with halo; heteroaryl; and C 1-4 alkyl.
  • Still an embodiment of the invention is related to compounds of formula I, wherein R 5 is selected from methyl;phenyl substituted by fluoro; CH 2 -OCH 3 ; CF 3 ; thiazol; imidazol; and -0-CH 2 -CHF 2 .
  • Still an embodiment of the invention is related to compounds of formula I, wherein A is mono- or di-substituted withone or more substituents R 5 .
  • One embodiment of the invention is related to compounds of formula I, wherein A is selected from: thiazolyl optionally substituted by methyl or fluorophenyl such as p-fiuorophenyl; pyridinyl optionally and independently mono- or di-substituted by methyl, -CH 2 -O-CH 3 , -OCH 2 CHF 2 , or CF 3 ; phenyl optionally substituted with thiazole or imidazole; quinolinyl; quinoxalinyl; and benzothiazolyl optionally substituted with fluoro;
  • R 1 and R 2 is each and independently selected from H; methyl; ethyl; propyl; i-propyl; butyl; cyclobutyl; -CH 2 -CH-(CH 3 ) 2 ; -CH 2 -CH 2 -CH 2 -OH (propanol); -CH 2 -(cyclopropyl).
  • Still an embodiment of the invention is related to compounds of formula I, wherein R 1 and R 2 together with N form a ring
  • Still an embodiment of the invention is related to compounds of formula I, wherein R 1 and R 2 together with N form an imidazolyl ring optionally substituted by a methyl group.
  • C m-n or "C m-n group” used alone or as a prefix, refers to any group having m to n carbon atoms.
  • alkyl used alone or as a suffix or prefix, refers to straight or branched chain hydrocarbyl radicals comprising 1 to about 6 carbon atoms.
  • cycloalkyl used alone or as suffix or prefix, refers to a saturated monovalent ring-containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms.
  • cycloalkyl refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system.
  • Cs. ⁇ cycloalkyl may be, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • alkyl refers to a divalent alkylene group.
  • alkoxy used alone or as a suffix or prefix, refers to radicals of the general formula -O-R, wherein R is an alkyl.
  • alkenyl used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 2 and up to about 12 carbon atoms.
  • alkynyl used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond and comprising at least 2 and up to about 12 carbon atoms.
  • 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 group having one or more polyunsaturated carbon rings of aromatic character, having from 5 to 14 carbon atoms.
  • C 6-10 aryl may without limitation be phenyl, naphthyl and the like.
  • cycloalkyl refers to a monovalent ring- containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms.
  • cycloalkyl refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system.
  • C 3 -i 2 cycloalkyl may be, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine radicals.
  • a “carbocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms.
  • heterocarbocyclyl or “heterocyclyl” refers to saturated or unsaturated carbocyclyl groups wherein one or more of the ring-forming atoms of the heterocarbocyclyl group is a heteroatom such as O, S, N, or P.
  • Heterocyclyl groups can be aromatic (e.g., "heteroaryl") or non-aromatic (e.g., "heterocycloalkyl”).
  • Heterocyclyl groups can correspond to fully hydrogenated and partially hydrogenated heteroaryl groups.
  • Heterocarbocyclyl groups can contain, in addition to at least one heteroatom, from about 1 to about 20 carbon atoms and can be attached through a carbon atom or heteroatom.
  • monocyclic heteroaryl and “bicyclic heteroaryl” refers to aromatic ring systems consisting of 1 and 2 rings, respectively, and comprising at least one heteroatom.
  • hydrocarbyl refers to any structure comprising only carbon and hydrogen atoms up to 14 carbon atoms.
  • 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.
  • 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.
  • One aspect of the present invention provides a process for preparing a compound of formula I or a salt thereof.
  • heterocyclic Chemistry J. A. Joule, K. Mills, G. F. Smith, 3 rd ed. Chapman and Hall (1995), p. 189- 224 and "Heterocyclic Chemistry", T. L. Gilchrist, 2 nd ed. Longman Scientific and Technical (1992), p. 248-282.
  • room temperature and “ambient temperature” shall mean, unless otherwise specified, a temperature between 16 and 25 0 C.
  • One embodiment of the invention relates to processes for the preparation of the compound of Formula I according to Methods A and B, comprising: Method A whereby the target compound of Formula Ia is obtained from the epoxide of formula II by treatment with a secondary or primary amine
  • R 1 to R 7 are as in Formula I or can be converted to such a group after the compound of Formula Ia is obtained.
  • the preparation of the epoxide (oxirane) can be executed by a number of methods known to the one skilled in the art.
  • the reaction conditions for the reaction of II to Ia can vary over a wide span but usually involve elevated temperatures up to 200 0 C which, for example, may be effected by heating in a microwave oven device.
  • Solvents are chosen to be compatible with such reacion conditions and are typically solvents such as THF, DMF or N-methyl-2-pyrrolidinone.
  • the epoxides of formula II can be prepared preferrably by reacting a ketone with a methylating agent such as a trimethylsulfonium salt or trimethylsulfoxonium salt in the presence of a base, for example sodium hydride or potassium t-butoxide, in a suitable solvent, for example DMF.
  • a base for example sodium hydride or potassium t-butoxide
  • a suitable solvent for example DMF.
  • Method B whereby the target compound of formula I is obtained from another compound of formula Ib via Ia by introducing the R 4 -R 7 substituents using standard methods described in the literature, for example by alkylating a secondary amine wherein R 6 is hydrogen with an alkyl halide, or by reacting a halide or trifiate of formula Ia, wherein any of the R 4 -R 7 substituents are bromide, iodide or trifiate, with an organometallic reagent such as an organozinc reagent in the presence of a suitable transition metal catalyst.
  • organometallic reagent such as an organozinc reagent in the presence of a suitable transition metal catalyst.
  • a variation of this method is to use an N-benzyl compound Ic under hydrogeno lytic conditions in methanol, preferrably in the presence of formaldehyde, or ethanol whereby the intermediate amine Ib is formed. This amine then undergoes reductive alkylation in the reaction mixture.
  • a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.
  • the pharmaceutical composition may be in a form suitable for oral administration, for example as a tablet, pill, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration e.g. as an ointment, patch or cream or for rectal administration e.g. as a suppository.
  • parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • a sterile solution suspension or emulsion
  • topical administration e.g. as an ointment, patch or cream
  • rectal administration e.g. as a suppository.
  • compositions may be prepared in a conventional manner using one or more conventional excipients, pharmaceutical acceptable diluents and/or inert carriers.
  • a suitable daily dose of a compound of the invention in the treatment of a mammal, including man, is approximately from 0.1 to 100 mg/kg bodyweight at peroral administration and from about 0.01 to 250 mg/kg bodyweight at parenteral administration.
  • the typical daily dose of the active ingredient varies within a wide range and will depend on various factors such as the relevant indication, severity of the illness being treated, the route of administration, the age, weight and sex of the patient and the particular compound being used, and may be determined by a physician. Medical Use
  • Compounds according to the present invention are contemplated to be useful in therapy.
  • Compounds of formula I as herein described and claimed, or a pharmaceutically acceptable salt thereof, as well as their corresponding active metabolites, exhibit a high degree of potency at the sodium channel NaVl .7 and also selectivity for this channel compared with other essential sodium channels. Accordingly, compounds of the present invention are expected to be useful in the treatment of conditions associated with upregulation of NaV 1.7 and other sodium channels present in C-fibers.
  • Compounds of the invention may be used to produce an inhibitory effect of sodium channels in mammals, including man.
  • One embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, in the manufacture of a medicament for the treatment of NaVl .7 mediated disorders.
  • Compounds of formula I according to the invention are expected to be useful for the treatment of a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout.
  • a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as
  • Still an aspect of the invention is the use of a compound of formula I, for the treatment of a vascular headache such as migraine.
  • Yet an aspect of the invention is the use of a compound of formula I, for the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder. Still an embodiment of the present invention is the use of a compound of formula I, for the treatment of epilepsy.
  • One embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, for the treatment of pain conditions related to arthritis, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis or ischeamic pain.
  • One embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, in therapy.
  • Still an embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, for the manufacture of a medicament for the treatment of a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout.
  • a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain
  • Still an aspect of the invention is the use of a compound of formula I, for the manufacture of a medicament for use in the treatment of a vascular headache such as migraine.
  • Yet an aspect of the invention is the use of a compound of formula I, for the manufacture of a medicament for use in the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder.
  • Still an embodiment of the present invention is the use of a compound of formula I, for the manufacture of a medicament for use in the treatment of of epilepsy.
  • Still an embodiment of the invention relates to a method for the treatment of any one of the following pain disorders such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or biliary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout; whereby a compound of formula I as hereinbefore defined, is administered to a subject in need of such treatment.
  • Still an aspect of the invention is a method for the treatment of a vascular headache such as migraine, whereby a compound of formula I as hereinbefore defined, is administered to a subject in need of such treatment.
  • Yet an aspect of the invention is a method for the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder, whereby a compound of formula I as hereinbefore defined, is administered to a subject in need of such treatment.
  • Still an embodiment of the present invention is a method for the treatment of epilepsy, whereby a compound of formula I as hereinbefore defined is administered to a subject in need of such treatment.
  • Yet an embodiment of the invention is a compound of formula I as hereinbefore defined, for use in the treatment of a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout.
  • Still an aspect of the invention is a compound of formula I as hereinbefore defined, for use in the treatment of a vascular headache such as migraine.
  • Yet an aspect of the invention is a compound of formula I as hereinbefore defined, for use in the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder.
  • Still an embodiment of the present invention is a compound of formula I as hereinbefore defined, for use in the treatment of epilepsy.
  • the term “therapy” and “treatment” includes prevention and prophylaxis, unless there are specific indications to the contrary.
  • the terms “treat”, “therapeutic” and “therapeutically” should be construed accordingly.
  • inhibitor and “antagonist” mean a compound that by any means, partly or completely, blocks the transduction pathway leading to the production of a response by the ligand.
  • disorder means any condition and/or disease associated with NaVl .7 activity.
  • Pain treatment as defined herein may be applied as a sole therapy or may involve, in addition to a compound according to the invention, administration of other analgesics or adjuvant therapy.
  • Such therapy may for example include in combination with a compound of the present invention, one or more of the following categories of pain-relieving ingredients:
  • opioid analgesics for example morphine, ketobemidone or fentanyl
  • analgesics of the NSAID or COX- 1/2 class for example ibuprofene, naproxene, celecoxib or acetylsalicylic acid, and their analogues containing nitric oxide- donating groups
  • analgesic adjuvants such as amitriptyline, imipramine, duloxetine or mexiletine
  • NMDA antagonists for example ketamine or dextrometorfan
  • sodium channel blocking agents for example lidocaine
  • anticonvulsants for example carbamazepine, topiramate or lamotrigine
  • anticonvulsant/analgesic amino acids such as gabapentin or pregabalin
  • cannabinoids cannabinoids.
  • Each active compound of such a combination may be administered simultaneously, separately or sequentiallly.
  • Step-1 Thiazole-2-carboxylic acid (5 g, 38.7 mmol) and CDMT (7.47 g, 42.6 mmol) were suspended in THF under N 2 at O 0 C. After 15 min NMM (11.7 g, 12.76 mL, 116 mmol) was added dropwise. The reaction mixture was stirred for 1.5 hr at RT, and then N- methoxymethanamine hydrochloride was added at 0 0 C. The reaction mixture was stirred over night at room temperature and was then concentrated under reduced pressure. The residue was redissolved in ethyl acetate and the solution was washed with water and brine, dried over anhydrous sodium sulfate. The residue after evaporation of solvents was purified by column chromatography eluting with 30% EtOAc/hexanes to give 4.6 g (70%) of the desired product as pale yellow oil.
  • the title compound was synthesized according to step 1-3 as described for IM-I starting from thiazole-2-carboxylic acid, and using 2-bromo-4-(2-fluoro-2-methyl-propyl)-l- methoxy-benzene in the second step.
  • the title compound was synthesized according to step 1-3 as described for IM-I starting from 5-(2,2-difiuoroethoxy)pyridine-2-carboxylic acid, and using 2-bromo-4-(2-fluoro-2- methyl-propyl)-l-methoxy-benzene in the second step.
  • Step-1 Methyl magnesium bromide (3M in diethyl ether) (30.5 mL, 91.4 mmol) was added to a solution of 4-methoxyphenyl acetone (5.0 g, 30.5 mmol) in anhydrous benzene (50 mL) under an athmosphere of nitrogen. The reaction mixture was stirred at 100 0 C for 3h. The reaction mixture was cooled on an ice bath and was carefully quenched with a saturated solution of ammonium chloride.
  • the aqueous layer was extracted with diethyl ether (2 x 50 mL) and the combined organic layer washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 5.4 g (98%) of the intermediate alcohol.
  • Step-2 (Diethylamino)sulfur trifiuoride (3.4 mL, 25.95 mmol) at -78 0 C, was added drop-wise to a solution of the intermediate alcohol from step 1 (1.76 g, 9.76 mmol) in anhydrous dichloromethane (20 mL). The reaction mixture was stirred at -78 0 C under an athmosphere of nitrogen for about 3h. The reaction was quenched with water (10 mL). The aqueous layer was extracted with dichloromethane (2x25 mL).
  • N-bromo-succinimide (6.65 g, 37.36 mmol) was added to a solution of the intermedate fluoro compound from step 2 (4.54 g, 24.9 mmol) in anhydrous acetonitrile (60 mL). The reaction mixture was stirred for 3h at room temperature. The reaction mixture was concentrated under reduced pressure to give the crude product which was purified by silica gel column chromatography using 10% ethyl acetate in hexane to yield 5.5 g (84%).
  • Trimethyl sulfoxonium iodide (Me 3 S(O)I )(130 mg, 0.59 mmol) was stirred in DMF (1 mL) under N 2 . After 10 min NaH (60% in mineral oil) ( 25 mg, 0.63 mmol) was added to the solution. The reaction mixture was stirred for 20 min before adding the (5-tert-Butyl-2- methoxy-phenyl)-quinolin-2-yl-methanone (100 mg, 0.31 mmol) dissolved in DMF (1 mL). After 30 min 3 mL of dimethylamine (2M solution in THF) was added and the reaction mixture was heated in microwave at 100 0 C for one hour.
  • reaction mixture was quenched with water and extracted with ether, the organic phase washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by column chromatography using a gradient of with 5 % methanol in dichloromethane to give 48 mg (42%) of the desired product.
  • 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.
  • 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 minutes.
  • a buffer rich in LiCl rich in LiCl for 60 minutes 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 affect such channels.
  • Electrophysiological studies can be performed using automated patch-clamp electrophysiology platforms, like Ion Works HT, Ion Works Quattro, PatchXpress, or any other suitable platform.
  • the cell line expressing the voltage-gated sodium channel of interest is plated in appropriate well tissue plates, as provided 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.
  • a suitable stimulus protocol may consist of eight voltage pulses, each to -20 mV and 50 ms in length, and separated from each other by 330 ms intervals at a potential of -90 mV, but may also have other suitable parameters.
  • Electrophysiological studies can also be performed using the whole cell configuration of the standard patch clamp technique as described in the literature.
  • cells that express the human 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.
  • This test is an accepted model of clinical pain in man, involving elements of nociceptor activation, inflammation, peripheral sensitization and central sensitization (A Tj ⁇ lsen et al. Pain 1992, 51, 5). It can therefore be inferred that a compound of the present invention is usefulas a therapeutic agent to relieve pain of various origins.
  • Compounds of formula I may showin analgesic activity in the intraarticular FCA (Freund's complete adjuvant) test in the rat, a model of inflammatory pain (Iadarola et al.

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Abstract

L'invention concerne des composés 1,1-diaryléthanol 2-substitués de formule I, qui sont des inhibiteurs du canal sodique NaVl.7, ainsi que l'utilisation de ces composés dans la fabrication de médicaments pour le traitement de douleurs.
PCT/SE2008/050789 2007-06-29 2008-06-27 Inhibiteurs à petites molécules de canaux sodiques navl.7 pour le traitement de douleurs WO2009005460A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013000651A1 (fr) 2011-06-27 2013-01-03 Newron Pharmaceuticals S.P.A. Dérivés d'arylalkylaminocarboxamides fluorés

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005097192A2 (fr) * 2004-04-05 2005-10-20 Laboratorios Del Dr. Esteve, S.A. Combinaison de substances actives
WO2006136821A1 (fr) * 2005-06-22 2006-12-28 Astex Therapeutics Limited Composes pharmaceutiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005097192A2 (fr) * 2004-04-05 2005-10-20 Laboratorios Del Dr. Esteve, S.A. Combinaison de substances actives
WO2006136821A1 (fr) * 2005-06-22 2006-12-28 Astex Therapeutics Limited Composes pharmaceutiques

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013000651A1 (fr) 2011-06-27 2013-01-03 Newron Pharmaceuticals S.P.A. Dérivés d'arylalkylaminocarboxamides fluorés

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