WO2004064835A1 - Utilisation d'agents de modulation du canal ionique pour traiter la douleur - Google Patents

Utilisation d'agents de modulation du canal ionique pour traiter la douleur Download PDF

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Publication number
WO2004064835A1
WO2004064835A1 PCT/DK2004/000019 DK2004000019W WO2004064835A1 WO 2004064835 A1 WO2004064835 A1 WO 2004064835A1 DK 2004000019 W DK2004000019 W DK 2004000019W WO 2004064835 A1 WO2004064835 A1 WO 2004064835A1
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alkyl
group
alkoxy
cycloalkyl
hydroxy
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PCT/DK2004/000019
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English (en)
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Bo Skaaning Jensen
Gordon John Blackburn-Munro
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Neurosearch A/S
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Publication of WO2004064835A1 publication Critical patent/WO2004064835A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen 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
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2

Definitions

  • the present invention relates to the use of a particular group of compounds, formerly known for their potassium channel modulating properties, as pain-relieving agents.
  • ion channels in particular Na + , VR1 , ASIC, and P2X 3 -channels
  • Normally sensory information acts at specialised ion channel complexes located upon C- or A ⁇ -sensory neuron endings to elicit noxious (pain-inducing) and non-noxious (non pain inducing) transmission to the CNS.
  • these same stimuli result in increased sensory transmission to the CNS due to the sensitising actions of peptides, cytokines and prostaglandins on ion channel function.
  • C-fibres transmit increased noxious information (hyperalgesia), and A ⁇ -fibres can also encode noxious information (allodynia).
  • WO 00/34248 describes chemical compounds capable of modulating potassium channels, and their use for the treatment or alleviation of diseases or conditions responsive to modulation of SKca.
  • IKca and/or BK channels including diseases or conditions like respiratory diseases, certain CNS-related diseases and for reducing or inhibiting undesired immunoregulatory actions.
  • migraine which is supposed relieved through their action on smooth muscles, these potassium channel modulators are not reported to have any potential for relieving pain.
  • potassium channels modulators a particular group of chemical compounds, formerly known as potassium channels modulators, are found useful for combating pain.
  • the invention relates to the use of chemical compounds of Formula I
  • R 3 , R 4 and R 5 independently of one another, represent hydrogen, alkyl, hydroxy, alkoxy, halo, NO 2 , CN, CF 3 , carboxy, or a group of the formula -SO2NR"R'", wherein R" and R" ⁇ independently of one another, represent hydrogen and/or alkyl; and/or a phenyl or benzyl group, which phenyl and benzyl groups may be substituted one or more times with substituents selected from halo, NO 2 , CN, CF 3) alkyl, cycloalkyl, hydroxy and alkoxy; or
  • R 5 is as defined above and R 3 and R 4 together form an additional 4 to 7 membered fused ring, which fused ring may be a carbocyclic or a heterocyclic ring, it may be an aromatic, saturated or partially saturated ring, and which fused ring may optionally be substituted one or more times with substituents selected from the group consisting of halo, NO 2 , CN, CF 3 , or a group of the formula -SO 2 NR"R" ⁇ wherein R" and R'", independently of one another, represent hydrogen and/or alkyl; for the manufacture of a pharmaceutical composition for the treatment or alleviation of pain.
  • the invention provides pharmaceutical compositions comprising the compounds for use according to the invention and methods for the treatment or alleviation of pain.
  • Other objects of the invention will be apparent to the person skilled in the art from the following detailed description and examples.
  • the pain-relieving compounds for use according to the invention may be characterised by Formula I,
  • X represents NR 2 , O or S;
  • R 2 represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, hydroxy- alkyl, alkoxy, alkoxy-alkyl, carboxy, -CH 2 CN, or a group of the formula -CH 2 CO 2 R', wherein R' represents hydrogen or alkyl; or a group of the formula -CH 2 CONR lv R v , wherein R ⁇ v and R v , independently of one another, represent hydrogen and/or alkyl; or a phenyl or a benzyl group, which phenyl and benzyl groups may be substituted one or more times with substituents selected from halo, NO 2 , CN, CF 3 , alkyl, cycloalkyl, hydroxy and alkoxy; and
  • R 3 , R 4 and R 5 independently of one another, represent hydrogen, alkyl, hydroxy, alkoxy, halo, NO 2 , CN, CF 3 , carboxy, or a group of the formula -SO 2 NR"R'", wherein R" and R" ⁇ independently of one another, represent hydrogen and/or alkyl; and/or a phenyl or benzyl group, which phenyl and benzyl groups may be substituted one or more times with substituents selected from halo, NO 2 , CN, CF 3 , alkyl, cycloalkyl, hydroxy and alkoxy; or
  • R 5 is as defined above and R 3 and R 4 together form an additional 4 to 7 membered fused ring, which fused ring may be a carbocyclic or a heterocyclic ring, it may be an aromatic, saturated or partially saturated ring, and which fused ring may optionally be substituted one or more times with substituents selected from the group consisting of halo, NO 2 , CN, CF 3 , or a group of the formula -SO 2 NR"R" ⁇ wherein R" and R'", independently of one another, represent hydrogen and/or alkyl.
  • X represents NR 2 , O or S.
  • R 1 and R 2 independently of one another, represent hydrogen and/or alkyl.
  • R 1 represents alkyl, cycloalkyl, cycloalkyl- alkyl, hydroxy, hydroxy-alkyl, alkoxy, alkoxy-alkyl, or a group of the formula -CH 2 CO 2 R', wherein R' represents hydrogen or alkyl; or a phenyl or benzyl group, which phenyl and benzyl groups may be substituted one or more times with substituents selected from halo, NO 2 , CN, CF 3 , alkyl, cycloalkyl, hydroxy and alkoxy; and R 2 represents hydrogen, alkyl, cycloalkyl, or a group of the formula -CH 2 CO 2 R', wherein R' represents hydrogen or alkyl; or a phenyl or benzyl group.
  • R 3 , R 4 and R 5 independently of one another, represent hydrogen, alkyl, hydroxy, alkoxy, halo, NO 2 , CN, CF 3 , carboxy, or a group of the formula -SO 2 NR"R'", wherein R" and R'", independently of one another, represent hydrogen and/or alkyl; and/or a phenyl or benzyl group, which phenyl and benzyl groups may be substituted one or more times with substituents selected from halo, NO 2 , CN, CF 3 , alkyl, cycloalkyl, hydroxy and alkoxy; or R 5 is as defined above and R 3 and R 4 together form an additional 4 to 7 membered fused ring, which fused ring may be a carbocyclic or a heterocyclic ring, it may be an aromatic, saturated or partially saturated ring, and which fused ring may optionally be substituted one or more times with substituents selected from the
  • R 3 , R 4 and R 5 independently of one another, represent hydrogen, alkyl, hydroxy, alkoxy, halo, NO 2 , CN, CF 3 , carboxy, phenyl and/or a group of the formula -SO 2 NR"R'", wherein R" and R'", independently of one another, represent hydrogen and/or alkyl; or R 5 is as defined above and R 3 and
  • R 4 together form an additional 5 to 6 membered fused ring, which fused ring may be a carbocyclic or a heterocyclic ring, it may be an aromatic, saturated or partially saturated ring, and which fused ring may optionally be substituted one or more times with substituents selected from the group consisting of halo, NO 2 , CN, CF 3 , or a group of the formula -SO 2 NR"R'", wherein R" and R'", independently of one another, represent hydrogen and/or alkyl.
  • R 5 represents hydrogen, alkyl, hydroxy, alkoxy, halo, NO 2 , CN, CF 3 or carboxy; and R 3 and R 4 together form an additional 5 to 6 membered, fused ring selected from cyclohexan, benzen, thiadiazol, piperidin and pyridin.
  • R 3 represents hydrogen, hydroxy, alkoxy, halo, NO2 or CF 3
  • R 4 represents hydrogen, alkoxy, halo, NO2, CN or CF 3
  • R 5 represents hydrogen, alkyl, NO 2 , halo or carboxy.
  • R 3 , R 4 and R 5 independently of one another, represent hydrogen, alkyl, halo, nitro, cyano and/or trifluoromethyl.
  • R 3 and R 4 independently of one another, represent hydrogen, halo, nitro, cyano and/or trifluoromethyl; and R 5 represents hydrogen.
  • the compound for use according to the invention is a benzimidazolone derivative represented by Formula II
  • R 1 represents alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, hydroxy-alkyl, alkoxy, alkoxy-alkyl, or a group of the formula -CH 2 CO 2 R ⁇ wherein R' represents hydrogen or alkyl; or a phenyl or benzyl group, which phenyl and benzyl groups may be substituted one or more times with substituents selected from halo, NO 2 . CN, CF 3 , alkyl, cycloalkyl, hydroxy and alkoxy; and
  • R 2 represents hydrogen, alkyl, cycloalkyl, or a group of the formula -CH2CO2R'.
  • R' represents hydrogen or alkyl; or a phenyl or benzyl group
  • R 3 , R 4 and R 5 independently of one another, represent hydrogen, alkyl, hydroxy, alkoxy, halo, NO 2 , CN, CF 3 , carboxy, phenyl and/or a group of the formula -SO 2 NR"R'", wherein R" and R"', independently of one another, represent hydrogen and/or alkyl.
  • the compound for use according to the invention is a compound of Formula II wherein R 1 represents a C- ⁇ - 6 -alkyl group; R 2 represents hydrogen, a C* ⁇ _ 6 -alkyl group or a cycloalkyl group; and R 3 and R 4 , independently of one another, represent halo, nitro, cyano and/or trifluoromethyl.
  • the compound for use according to the invention is 1-Ethyl-4,5-dichlorobenzimidazol-2-one; or
  • the compound for use according to the invention is a compound of Formula I wherein X represents O or S;
  • R 1 represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, hydroxy- alkyl, alkoxy, alkoxy-alkyl, or a group of the formula -CH 2 CO 2 R', wherein R' represents hydrogen or alkyl; or a phenyl or benzyl group, which phenyl and benzyl groups may be substituted one or more times with substituents selected from halo, NO 2 , CN, CF 3 , alkyl, cycloalkyl, hydroxy and alkoxy;
  • R 2 represents hydrogen, alkyl, cycloalkyl, phenyl, benzyl, or a group of the formula -CH 2 CO 2 R', wherein R' represents hydrogen or alkyl;
  • R 3 , R 4 and R 5 independently of one another, represent hydrogen, alkyl, hydroxy, alkoxy, halo, NO 2 , CN, CF 3 , carboxy, phenyl and/or a group of the formula -SO 2 NR"R'", wherein R" and R'", independently of one another, represent hydrogen and/or alkyl; or R R 55 iiss as defined above and R 3 and R 4 together form an additional 5 to 6 membered fused ring, which fused ring may be a carbocyclic or a heterocyclic ring, it may be an aromatic, saturated or partially saturated ring, and which fused ring may optionally be substituted one or more times with substituents selected from the group consisting of halo, NO 2 , CN, CF 3 , or a group of the formula -SO 2 NR"R'", wherein R" and R'", independently of one another, represent hydrogen and/or alkyl.
  • R 1 represents alkyl, cycloalkyl, cycloalkyl-alkyl or benzyl
  • R 2 represents hydrogen, alkyl or cycloalkyl
  • R 3 , R 4 and R 5 independently of one another, represent hydrogen, alkyl, hydroxy, alkoxy, halo, NO 2 , CN, CF 3> carboxy and/or phenyl.
  • the compound for use according to the invention is a compound of Formula I wherein R 3 and R 4 together form a fused pyridine ring, which pyridine ring may optionally be substituted one or more times with substituents selected from the group consisting of halo, NO 2 , CN and CF 3 .
  • the compound for use according to the invention is a compound of Formula I wherein R 1 and R 2 , independently of one another, represent hydrogen and/or alkyl; and R 5 represents hydrogen.
  • X, R 1 and R 5 are as defined in claim 1 ; and Y represents hydrogen, halo, NO , CN, CF 3 , or a group of the formula -SO 2 NR"R'", wherein R" and R"', independently of one another, represent hydrogen and/or alkyl.
  • the compound for use according to the invention is a compound of Formula III wherein X represents NR 2 or O; R 1 and R 2 , independently of one another, represent hydrogen and/or alkyl; and R 5 represents hydrogen.
  • the compound for use according to the invention is 5,6,7,8-Tetrahydronaphto[1 ,2-d]imidazolinone;
  • X, R 1 and R 5 are as defined above; and Y represents hydrogen, halo, NO 2 , CN, CF, or a group of the formula
  • R" and R' independently of one another, represent hydrogen and/or alkyl.
  • the compound for use according to the invention is a compound of Formula IV, wherein X represents NR 2 or O; R 1 and R 2 , independently of one another, represent hydrogen and/or alkyl; and R 5 represents hydrogen.
  • the compound for use according to the invention is a compound of Formula I, wherein R 3 and R 4 together form a 5 - membered heterocyclic fused ring, which fused ring may optionally be substituted one or more times with substituents selected from the group consisting of halo, NO2, CN and CF 3 .
  • the heterocyclic ring is a 1 ,2 or 4- imidazolyl, 1,2,3,4- or 2,1,3,4-tetrazolyl, thiadiazol-3,4 or 5-yl, thiazol-2,4 or 5-yl, or 2 or 3-thienyl.
  • R 1 and R 2 independently of one another, represent hydrogen, alkyl and/or benzyl; and R 5 represents hydrogen.
  • halo represents a fluorine, a chlorine, a bromine or a iodine atom.
  • an alkyl group designates a univalent saturated, straight or branched hydrocarbon chain.
  • the hydrocarbon chain preferably contain of from one to twelve carbon atoms (C ⁇ - 12 -alkyl), more preferred of from one to six carbon atoms (C- ⁇ _ 6 -alkyl; lower alkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl.
  • alkyl represents a C- ⁇ -4-alkyl group, including butyl, isobutyl, secondary butyl, and tertiary butyl.
  • alkyl represents a C*i- 3 -alkyl group, which may in particular be methyl, ethyl, propyl or isopropyl.
  • a cycloalkyl group designates a cyclic alkyl group, preferably containing of from three to seven carbon atoms (C 3 _ -cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • a cycloalkyl-alkyl group designates a cycloalkyl group as defined above, which cycloalkyl group is substituted on an alkyl group as also defined above.
  • Examples of preferred cycloalkyl-alkyl groups of the invention include cyclopropylmethyl and cyclopropylethyl.
  • a hydroxy-alkoxy group designates an alkoxy group as defined above, which alkoxy group is substituted with one or more hydroxy groups.
  • Preferred hydroxy-alkoxy groups of the invention include 2-hydroxy- ethoxy, 3-hydroxy-propoxy, 4-hydroxy-butoxy, 5-hydroxy-pentoxy and 6-hydroxy- hexoxy.
  • an alkoxy group designates an "alkyl-O-" group, wherein alkyl is as defined above.
  • alkoxy-alkyl group designates an "alkyl- O-alkyl-" group, wherein alkyl is as defined above.
  • alkoxy-alkyl groups of the invention include methoxy-methyl, methoxy-ethyl, ethoxy-methyl, and ethoxy-ethyl.
  • a carbocyclic ring is a group holding carbon only as ring atom.
  • the ring structure may in particular be aromatic (i.e. a benzene ring), or a saturated 5-6 membered cycloalkane ring.
  • a heterocyclic group is a cyclic group, which holds one or more heteroatoms in its ring structure. Preferred heteroatoms include nitrogen (N), oxygen (O), and sulphur (S).
  • the ring may in particular be aromatic (i.e. a heteroaryl), saturated or partially saturated.
  • Preferred heterocyclic monocyclic groups of the invention include 5- and 6 membered heterocyclic monocyclic groups.
  • Examples of preferred aromatic heterocyclic monocyclic groups of the invention include 1,3,2,4- or 1,3,4,5-dioxadiazolyl, dioxatriazinyl, dioxazinyl, 1 ,2,3-, 1 ,2,4-, 1 ,3,2- or 1 ,3,4-dioxazolyl, 1 ,3,2,4- or 1 ,3,4,5-dithiadiazolyl, dithiatriazinyl, dithiazinyl, 1 ,2,3-dithiazolyl, 2- or 3-furanyl, furazanyl, 1 ,2 or 4-imidazolyl, isoindazolyl, isothiazol-3,4 or 5-yl, isoxazol-3,4 or 5-yl, 1 ,2,3-, 1 ,2,4-, 1 ,2,5- or 1 ,3,4-oxadiazol-3,4 or 5-yl, oxatetrazinyl, oxatriazinyl,
  • heterocyclic groups are 1,2 or 4-imidazolyl, 1,2,3,4- or 2,1 ,3,4- tetrazolyl, thiadiazol-3,4 or 5-yl, thiazol-2,4 or 5-yl, and 2 or 3-thienyl.
  • Examples of preferred saturated or partially saturated heterocyclic monocyclic groups of the invention include 1 ,3,5,6,2-dioxadiazinyl, 1 ,2,3,4,5-, 1 ,2,3,5,4-dioxadiazolyl, dioxanyl, 1 ,3-dioxolyl, 1 ,3,5,6,2-dithiadiazinyl, 1 ,2,3,4,5- or 1 ,2,3,5,4-dithiadiazolyl, 2-isoimidazolyl, isopyrrolyl, isotetrazolyl, 1 ,2,3- or 1 ,2,4- isotriazolyl, morpholinyl, oxadiazinyl, 1 ,2,4-, 1 ,2,6-, 1 ,3,2-, 1 ,3,6- or 1 ,4,2-oxazinyl, piperazinyl, homopiperazinyl, piperidinyl, 1 ,2-, 1 ,3- or 1 ,4-pyranyl,
  • the pain-relieving compounds of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre- or prodrug forms of the chemical compound of the invention.
  • pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the acetate derived from acetic acid, the aconate derived from aconitic acid, the ascorbate derived from ascorbic acid, the benzenesulfonate derived from benzensulfonic acid, the benzoate derived from benzoic acid, the cinnamate derived from cinnamic acid, the citrate derived from citric acid, the embonate derived from embonic acid, the enantate derived from enanthic acid, the formate derived from formic acid, the fumarate derived from fumaric acid, the glutamate derived from glutamic acid, the glycolate
  • Metal salts of pain-relieving compounds for use according to the invention includes alkali metal salts, such as the sodium salt of a chemical compound of the invention containing a carboxy group.
  • the pain-relieving compounds for use according to the invention may be provided in unsolved or solvated forms together with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • Solvated forms may also include hydrated forms such as the monohydrate, the dihydrate, the hemihydrate, the trihydrate, the tetrahydrate, and the like. In general, solvated forms are considered equivalent to unsolved forms for the purposes of this invention.
  • the pain-relieving compounds for use according to the invention may exist in (+) and (-) forms as well as in racemic forms.
  • the racemates of these isomers and the individual isomers themselves are within the scope of the present invention.
  • Racemic forms can be resolved into the optical antipodes by known methods and techniques. One way of separating the diastereomeric salts is by use of an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optical active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallisation of d- or I- (tartrates, mandelates, or camphorsulphonate) salts for example.
  • the pain-relieving compound for use according to the invention may also be resolved by the formation of diastereomeric amides by reaction of the pain-relieving compound with an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic acid or by the formation of diastereomeric carbamates by reaction of the pain-relieving compound for use according to the invention with an optically active chloroformate or the like. Additional methods for the resolving the optical isomers are known in the art. Such methods include those described by Jaques J, Collet A, & Wilen S in "Enantiomers. Racemates. and Resolutions". John Wiley and Sons, New York (1981).
  • C- fibres which mechanism may be - without limiting the scope of the invention - the mechanism by which they act as pain-relieving agents.
  • the pain-relieving activity of the compounds for use according to the invention may be determined by standard methods, e.g. Stein et al., Pharmacol. Biochem. Behav. 1988 31 445-451 ; Bennett GJ et al., Pain 1988 33 87-107; Kingery et al., Pain 1989 38 321-322; Seltzer et al., Pain 1990 43 205-218; Wheeler-Aceto et al., Psvchopharmacology 1991 104 35; Chung et al., Pain 1992 50 355-363; Chaplan SR et al., J. Neurosci. Methods 1994 53 55-63; and Mosconi Tet al., Pain 1996 64 37-57.
  • the realisation of pain is a multi-dimensional process involving physical, emotional and perceptual integration, the primary function of which is to serve to protect the organism from a potentially tissue-damaging stimulus. .
  • the pain treated or alleviated according to the invention may in particular be
  • Nociceptive pain which is the normal (reflex) physiological response to pain. This type of pain occurs with any form of acute pain such as a sharp needle prick against the skin; Inflammatory pain, which is usually triggered by nociceptive afferents that become irritated when surrounded by inflamed tissue. In most cases, pain sensitivity is proportional to the degree of inflammation and pain generally decreases when the injury heals although the arthritic disorders (osteoarthritis, rheumatoid arthritis) are often an exception to this point. Inflammatory pain also includes fibromyalgia, back pain, cancer pain, irritable bowel pain, post-operative pain, pain associated with viral infection or diseases, with a recognised peripheral or central inflammatory component;
  • Neuropathic pain which usually occurs specifically from nerve injury, and which may persist even after the injured nerve has healed, outliving its biological usefulness and compromising the quality of life for the individual.
  • Neuropathic pain is usually associated with e.g. pain arising from any disease state causing damage to the peripheral or central nervous systems, back pain, cancer pain, chemotherapy induced neuropathy, postherpetic neuralgia, fibromyalgia, trigeminal neuralgia, diabetic neuropathy, multiple sclerosis and AIDS pain;
  • Neurogenic pain which usually involves dysfunction within the PNS or CNS, and which usually occurs without inflammation, nociception or any particular trauma; and
  • the pain may be acute or chronic pain.
  • chronic pain is a ubiquitous term generally defined as pain that persists beyond the usual course of an acute disease, or beyond a reasonable time for an injury to heal that recurs at intervals of months or years.
  • migraine is not considered a condition for treatment or alleviation according to the invention, because migraine is believed to be relieved through an action on the smooth muscles.
  • the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of a pain-relieving compounds for use according to the invention.
  • a pain-relieving compound for use according to the invention may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
  • the invention provides pharmaceutical compositions comprising the SK/IK/BK channel modulating agents of the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers therefor, and, optionally, other therapeutic and/or prophylactic ingredients, know and used in the art.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.
  • Pharmaceutical compositions of the invention may be those suitable for oral, rectal, bronchial, nasal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, and intravenous injection) administration, or those in a form suitable for administration by inhalation or insufflation.
  • the pain-relieving compound together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof.
  • Such forms include solids, and in particular tablets, filled capsules, powder and pellet forms, and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with the same, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the pain-relieving compound for use according to the invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a chemical compound of the invention or a pharmaceutically acceptable salt of a chemical compound of the invention.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glyceride or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • the pain-relieving compound for use according to the invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g. sterile, pyrogen-free water
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • liquid form preparations intended for conversion shortly before use to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pain-relieving compound may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
  • compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the compositions may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
  • compositions adapted to give sustained release of the active ingredient may be employed.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
  • a therapeutically effective dose refers to that amount of active ingredient which ameliorates the symptoms or condition.
  • Therapeutic efficacy and toxicity e.g. ED 50 and LD 50 , may be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index and may be expressed by the ratio LD 5 o/EDs 0 . Pharmaceutical compositions which exhibit large therapeutic indexes are preferred.
  • compositions containing of from about 0.1 to about 500 mg of active ingredient per individual dose, preferably of from about 1 to about 100 mg, most preferred of from about 1 to about 10 mg, are suitable for therapeutic treatments.
  • the active ingredient may be administered in one or several doses per day. A satisfactory result can, in certain instances, be obtained at a dosage as low as 0.1 ⁇ g/kg i.v. and 1 ⁇ g/kg p.o.
  • the upper limit of the dosage range is presently considered to be about 10 mg/kg i.v. and 100 mg/kg p.o.
  • Preferred ranges are from about 0.1 ⁇ g/kg to about 10 mg/kg/day i.v., and from about 1 ⁇ g/kg to about 100 mg/kg/day p.o.
  • the invention provides a method for the treatment or alleviation of pain in living animals, including humans, which method comprises administering to such a living animal body, including a human, in need thereof an effective amount of a pain-relieving compound as described above.
  • the pain for treatment or alleviation according to the invention may in particular be nociceptive pain, inflammatory pain, neuropathic pain, neurogenic pain, acute pain or chronic pain.
  • suitable dosage ranges are 0.1 to 1000 milligrams daily, 10-500 milligrams daily, and especially 30-100 milligrams daily, dependent as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.

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

Abstract

L'invention concerne l'utilisation d'un groupe particulier de composés, connus pour leurs propriétés de modulation du canal potassique, en tant qu'analgésiques.
PCT/DK2004/000019 2003-01-17 2004-01-16 Utilisation d'agents de modulation du canal ionique pour traiter la douleur WO2004064835A1 (fr)

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DKPA200300044 2003-01-17

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1719761A1 (fr) * 2004-02-23 2006-11-08 Dainippon Sumitomo Pharma Co., Ltd. Nouveau compose heterocyclique
EP1958947A1 (fr) 2007-02-15 2008-08-20 Ranbaxy Laboratories Limited Inhibiteurs de la phosphodiestérase de type 4

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EP0545845A1 (fr) * 1991-12-03 1993-06-09 Neurosearch A/S Composés d'imidazole, leur préparation et utilisation comme inhibiteurs du canal calcique
EP0872246A1 (fr) * 1995-11-30 1998-10-21 Kissei Pharmaceutical Co., Ltd. Nouveau medicament pour attenuer la douleur et favoriser l'elimination des calculs lies a l'urolithiase
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1719761A1 (fr) * 2004-02-23 2006-11-08 Dainippon Sumitomo Pharma Co., Ltd. Nouveau compose heterocyclique
EP1719761A4 (fr) * 2004-02-23 2007-10-10 Dainippon Sumitomo Pharma Co Nouveau compose heterocyclique
EP1958947A1 (fr) 2007-02-15 2008-08-20 Ranbaxy Laboratories Limited Inhibiteurs de la phosphodiestérase de type 4

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