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WO2004035056A1 - Utilisation de medicaments bloquant les canaux skca pour lutter contre la maladie de parkinson - Google Patents

Utilisation de medicaments bloquant les canaux skca pour lutter contre la maladie de parkinson Download PDF

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Publication number
WO2004035056A1
WO2004035056A1 PCT/DK2003/000678 DK0300678W WO2004035056A1 WO 2004035056 A1 WO2004035056 A1 WO 2004035056A1 DK 0300678 W DK0300678 W DK 0300678W WO 2004035056 A1 WO2004035056 A1 WO 2004035056A1
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alkyl
group
use according
pharmaceutically
formula
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PCT/DK2003/000678
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English (en)
Inventor
Karin Sandager Nielsen
Lene Teuber
Bo Skaaning Jensen
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Neurosearch A/S
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Application filed by Neurosearch A/S filed Critical Neurosearch A/S
Priority to AU2003271548A priority Critical patent/AU2003271548A1/en
Publication of WO2004035056A1 publication Critical patent/WO2004035056A1/fr

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • This invention relates to the use of compounds capable of inhibiting the activity of small conductance calcium activated potassium channels for the treatment, prevention or alleviation of Parkinson's disease, or for controlling movement of a Parkinsonian patient.
  • Parkinson's disease is a progressive neurodegenerative disease characterised by increasing difficulties in initiating movement, rigidity in arms and legs, as well as tremors.
  • the aetiology of PD is still unknown.
  • the SKca channel family includes the SKc a channel subunits SK ⁇ , SK 2 and SK 3 .
  • the distribution of S ⁇ and SK 2 show a high degree of overlap and display the highest levels of expression in neocortical, limbic and hippocampal areas in the rat brain.
  • the SK 3 channels show high levels of expression in the brain stem monoaminergic neurons (dorsal raphe, locus coeruleus and the ventral tegmental area), with the highest expression found in the dopaminergic neurons of the substantia nigra.
  • a similar distribution has been found in human tissue, where the relative levels of expression of the three channels are reported to be SK 3 >SK 2 >SK- ⁇ .
  • WO 98/11139 (Oregon Health Sciences University) discloses isolated DNA coding small and intermediate conductance calcium activated potassium channels, in particular SKc a channel subunits SK-i, SK 2 and SK 3 , and report various diseases associated with this channel. PD, however, is not described as a disease relevant to this potassium channel.
  • WO 99/03889 (University of California) discloses isolated DNA coding human, small conductance calcium activated potassium channel (SKca channel subunit SK 3 ) and report various diseases associated with this channel. PD, however, is not described as a disease relevant to this potassium channel.
  • WO 02/36121 (Glaxo Group Ltd.) discloses the use of openers of calcium activated potassium channels, in particular SKc a channel subunit SK 3 , in the treatment of bipolar disorder. No activity useful for combating PD is reported.
  • WO 97/48705 discloses a particular group of chemical compounds useful as calcium activated potassium channel blocking agents. No activity useful for combating PD is reported.
  • WO 01/02406 discloses cyclic bis-amino-quinazolines useful as potassium channel blocking agents. No activity useful for combating PD is reported.
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound capable of inhibiting the activity ("blocking") of a human small conductance calcium activated potassium channel (SKca channel) at a micomolar concentration (i.e. an SK Ca channel blocker), or a pharmaceutically-acceptable addition salt thereof, together with at least one pharmaceutically-acceptable carrier or diluent, for the treatment, prevention or alleviation of Parkinson's disease, or for controlling movement of a Parkinsonian patient.
  • the invention relates to the use of a compound capable of inhibiting the activity ("blocking") of a human small conductance calcium activated potassium channel (SKca channel) at a micomolar concentration (i.e. an SKca channel blocker), or a pharmaceutically-acceptable addition salt thereof, for the manufacture of a medicament for the treatment, prevention or alleviation of Parkinson's disease, or for controlling movement of a Parkinsonian patient.
  • the invention privodes a method of treatment, prevention or alleviation of Parkinson's disease, or for controlling movement of a Parkinsonian patient, which method comprises the step of administering to such a patient a therapeutically effective amount of a compound capable of inhibiting the activity ("blocking") of a human small conductance calcium activated potassium channel (SKca channel) at a micomolar concentration (i.e. an SKc a channel blocker), or a pharmaceutically-acceptable addition salt thereof.
  • SKca channel human small conductance calcium activated potassium channel
  • micomolar concentration i.e. an SKc a channel blocker
  • the present invention relates to the use of a chemical compound having
  • SKca inhibitory activity for treatment or alleviation of diseases or conditions relating to Parkinson's disease.
  • an SKc a blocking compound is a chemical compound having SKc a inhibitory activity, identified by its ability to inhibit hyperpolarization of an SKca containing cell, i.e. a cell containing a small conductance
  • SK Ca channel Ca 2+ activated potassium channel
  • Preferred SKca blocking compounds of the invention are selective towards SKc a channel subunit SK 3 .
  • the ability of a particular compound to inhibit hyperpolarization of an SKc a containing cell may be determined by standard methods known in the art, e.g. the assay described in Example 2 of WO 01/02406 (NeuroSearch).
  • Preferred SKca blocking compounds for use according to the invention show SKc a blocking activity at a micromolar concentration, more preferred at a concentration in the low micromolar, i.e. of below 100 ⁇ M, or nanomolar range, i.e. of below 1 ⁇ M.
  • SKc a blocking compound for use according to the invention are those compounds described in WO 01/02406 (NeuroSearch), WO 97/48705 (University College London), US 5739127, US 5760230 and US 5874438 (Bayer AG).
  • the SKc a blocking compounds for use according to the invention also show a monoamine reuptake inhibitory activity, such as a dopamine reuptake inhibitory activity.
  • the SK Ca blocking compounds for use according to the invention also show a monoamine reuptake inhibitory activity at a micromolar concentration, more preferred at a concentration in the low micromolar, i.e. of below 100 ⁇ M, or nanomolar range, i.e. of below 1 ⁇ M.
  • the SKca blocking compound for use according to the invention is a bridged or cyclic amino-imidazole derivative represented by Formula IA or IB,
  • IVA, IVB or IVC are IVA, IVB or IVC.
  • a and B independently of each another, represent a linking group having a linear or branched alkylene chain having of from 1 to 20 carbon atoms, preferably of from 3 to 15 carbon atoms; and R 1 , R 2 , R 3 and R 4 , independently of each another, represent hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, haloalkyl, hydroxy, alkoxy, amino, nitro, cyano, phenyl, phenoxy or benzyl; or
  • R', R", R'", R"", R * , R* * , R * * and R * *** independently of each another, represent hydrogen, alkyl or phenyl; or R' and R'", and/or R" and R"", form a C ⁇ . 10 -methylene linker, and the remaining of R', R", R'", R"", R*, R ** , R * * * and R ** ** are as defined above; or
  • R * and R ** , and/or R *** and R **** together with the nitrogen atom to which they are attached form a monocyclic, heterocyclic group, optionally containing nitrogen, oxygen or sulfur as additional heteroatoms, and the remaining of R', R", R'", R"", R * , R ** , R *** and R **** are as defined above; or R * and R***, and/or R** and R **** , form a C ⁇ o-methylene linker, and the remaining of R', R", R'", R"", R*, R**, R* ** and R **** are as defined above.
  • the SKca blocking compound for use according to the invention is a bridged or cyclic amino-benzimidazole derivative represented by Formula VA or VB,
  • VMA or VMB VMA or VMB
  • R 5 , R 6 , R 7 and R 8 independently of each another, represent hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, haloalkyl, hydroxy, alkoxy, amino, nitro, cyano, phenyl, phenoxy or benzyl; and
  • A, B, R', R", R'", R"", R * , R* * , R * * * and R *** * are as defined above.
  • a and B independently of each another, represent a C ⁇ - ⁇ 0 -methylene linker; or a -Co- 3 -alkyl-"CYC"-Co- 3 -alkyl- linker, wherein "CYC" represents a monocyclic saturated or unsaturated carbocyclic group.
  • the C-i.-io-methylene linker is methylene, dimethylene; trimethylene; tetramethylene; pentamethylene; hexamethylene; octamethylene; or decamethylene.
  • the "CYC" represents a C 3 . -cycloalkyl group or a phenyl group.
  • the -C 0 - 3 -alkyl-"CYC"-C 0 -3-alkyl- linker is (cis and/or trans)-1 ,3-cyclohexane-diyl, (cis and/or trans)-1 ,3-dimethylcyclohexane- ⁇ , ⁇ '- diyl, (cis and/or trans)-1 ,4-dimethylcyclohexane- ⁇ , ⁇ '-diyl, para-xylene- ⁇ . ⁇ '-diyl, meta- xylene- ⁇ , ⁇ '-diyl or 1 ,3-phenylene.
  • R * and R ** , and/or R*** and R**** together with the nitrogen atom to which they are attached form a pyrrolidine group, a piperidine group, a morpholine group or a piperazine group.
  • SKca blocking compound of Formula VIB for use according to the invention is
  • SK Ca blocking compound of Formula VIIIA for use according to the invention is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-a pharmaceutically-acceptable addition salt thereof.
  • the SK Ca blocking compound of Formula VII IB for use according to the invention is
  • halogen represents a fluorine, a chlorine, a bromine or an iodine atom.
  • an alkyl group designates a univalent saturated, straight or branched hydrocarbon chain.
  • the hydrocarbon chain preferably contain of from one to eighteen carbon atoms (C-i-ie-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 Chalky! group, including butyl, isobutyl, secondary butyl, and tertiary butyl.
  • alkyl represents a C ⁇ . 3 -alkyl group, which may in particular be methyl, ethyl, propyl or isopropyl.
  • an alkenyl group designates a carbon chain containing one or more double bonds, including di-enes, tri-enes and poly-enes.
  • the alkenyl group of the invention comprises of from two to eight carbon atoms (C 2 . 8 -alkenyl), more preferred of from two to six carbon atoms (C 2 - 6 -alkenyl), including at least one double bond.
  • the alkenyl group of the invention is ethenyl; 1- or 2-propenyl (allyl); 1-, 2- or 3-butenyl, or 1 ,3-butdienyl; 1-, 2-, 3-, 4- or 5-hexenyl, or 1 ,3-hexdienyl, or 1 ,3,5-hextrienyl; 1-, 2-, 3-, 4-, 5-, 6-, or 7-octenyl, or 1 ,3-octdienyl, or 1 ,3,5-octtrienyl, or 1 ,3,5,7-octtetraenyl.
  • an alkynyl group designates a carbon chain containing one or more triple bonds, including di-ynes, tri-ynes and poly-ynes.
  • the alkynyl group of the invention comprises of from two to eight carbon atoms (C 2 - 8 -alkynyl), more preferred of rom two to six carbon atoms (C 2 - 6 - alkynyl), including at least one triple bond.
  • the alkynyl group of the invention is ethynyl; 1-, or 2-propynyl; 1-, 2-, or 3-butynyl, or 1 ,3- butdiynyl; 1-, 2-, 3-, 4-pentynyl, or 1 ,3-pentdiynyl; 1-, 2-, 3-, 4-, or 5-henynyl, or 1 ,3- hexdiynyl or 1 ,3,5-hextriynyl; 1-, 2-, 3-, 4-, 5- or 6-heptynyl, or 1 ,3-heptdiynyl, or 1 ,3,5- hepttriynyl; 1-, 2-, 3-, 4-, 5-, 6- or 7-octynyl, or 1 ,3-octdiynyl, or 1 ,3,5-octtriynyl, or 1 ,3,5,7-octtetrayny
  • a cycloalkyl group designates a cyclic alkyl group, preferably containing of from three to seven carbon atoms (C 3 . -cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • 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 haloalkyl group designates an alkyl group as defined herein, which alkyl group is substituted one or more times with halogen.
  • Preferred haloalkyl groups of the invention include trihalogenmethyl.
  • an alkoxy group designates an "alkyl-O-" group, wherein alkyl is as defined above.
  • alkyl is as defined above.
  • preferred alkoxy groups of the invention include methoxy and ethoxy.
  • an amino group may be a primary (-NH 2 ), secondary (-NH-alkyl), or tertiary (-N(alkyl) 2 ) amino group, i.e. it may be substituted once or twice with an alkyl group as defined above.
  • the chemical compound 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 hydro- chloride derived from hydrochloric acid, the hydrobromide derived from hydrobromic acid, the nitrate derived from nitric acid, the perchlorate derived from perchloric acid, the phosphate derived from phosphoric acid, the sulphate derived from sulphuric acid, the formate derived from formic acid, the acetate derived from acetic acid, the aconate derived from aconitic acid, the ascorbate derived from ascorbic acid, the benzenesul- phonate derived from benzensulphonic acid, the benzoate derived from benzoic acid, the c
  • oxalic acid which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable cationic salts of a chemical compound of the invention include, without limitation, the sodium, the potassium, the calcium, the magnesium, the zinc, the aluminium, the lithium, the choline, the lysine, and the ammonium salt, and the like, of a chemical compound of the invention containing an anionic group.
  • Such cationic salts may be formed by procedures well known and described in the art.
  • onium salts of N-containing compounds are also contemplated as pharmaceutically acceptable salts.
  • Preferred “onium salts” include the alkyl-onium salts, the cycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.
  • 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 chemical compounds of the present invention may also be resolved by the formation of diastereomeric amides by reaction of the chemical compounds of the present invention 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 chemical compound of the present 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).
  • Optical active compounds can also be prepared from optical active starting materials.
  • the compounds of the invention may be obtained by conventional methods for chemical synthesis, e.g. those described in described in WO 01/02406 (NeuroSearch), WO 97/48705 (University College London), US 5739127, US 5760230 and US 5874438 (Bayer AG).
  • the invention provides novel pharmaceutical compositions a therapeutically effective amount of a compound capable of inhibiting the activity ("blocking") of a human small conductance calcium activated potassium channel (SKc a channel) at a micromolar concentration (i.e. an SKc a channel blocker), or a pharmaceutically-acceptable addition salt thereof, together with at least one pharmaceutically-acceptable carrier or diluent, for the treatment, prevention or alleviation of Parkinson's disease, or for controlling movement of a Parkinsonian patient.
  • SKc a channel a human small conductance calcium activated potassium channel
  • a micromolar concentration i.e. an SKc a channel blocker
  • a pharmaceutically-acceptable addition salt thereof i.e. an SKc a channel blocker
  • a chemical compound of the invention for use in therapy 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 chemical compound of the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers therefore, 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.
  • compositions of the invention may be those suitable for oral, rectal, bronchial, nasal, pulmonal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for administration by inhalation or insuffla- tion, including powders and liquid aerosol administration, or by sustained release systems.
  • sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the invention, which matrices may be in form of shaped articles, e.g. films or microcapsules.
  • compositions and unit dosages thereof may thus be placed into the form of pharmaceutical compositions and unit dosages thereof.
  • 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 chemical compound of the present 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 as- sociation 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 chemical compound according to the present 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, stabilis- ing 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.
  • 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.
  • solid form preparations intended for conversion shortly before use to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • preparations may comprise colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the chemical compound of the invention 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.
  • 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 dichlorodi- fluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodi- fluoromethane, 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 hydroxypropyl methyl cellulose and polyvi- nylpyrrolidone (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropyl methyl cellulose and polyvi- nylpyrrolidone (PVP).
  • PVP polyvi- nylpyrrolidone
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in cap- sules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the compound In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for ex- ample 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.
  • compositions for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions. Further details on techniques for formulation and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).
  • 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 50 /ED 50 . Pharmaceutical compositions exhibiting 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, prevention or alleviation of Parkinson's disease, or for controlling movement of a Parkinsonian patient, which method comprises the step of administering to such a patient a therapeutically effective amount of a compound capable of inhibiting the activity ("blocking") of a human small conductance calcium activated potassium channel (SKca channel) at a micomolar concentration (i.e. an SKc a channel blocker), or a pharmaceutically-acceptable addition salt thereof.
  • SKca channel a human small conductance calcium activated potassium channel
  • micomolar concentration i.e. an SKc a channel blocker
  • a compound capable of selectively inhibiting the activity of a human small conductance calcium activated potassium channel subunit SK 3 is administered.
  • the SK Ca channel blocker 1 ,3-Bis-[(2-diethylamino-4- quinazolyl)-aminomethyl]-cyclohexane (the test compound) was used.
  • the test compound was obtained according to Example 1 of US 5760230.
  • the animals were injected s.c. with Rimadyl (5 mg/kg) prior to incision. The animals were allowed a minimum of 14 days of recovery before behavioural testing took place. All animals were primed with one injection of Apomorphine (0.05 mg/kg, s.c.) before drug testing. On the day of testing, the animals were injected with Benserazide (10 mg/kg, i.p) and a sub-threshold dose of L-DOPA (2 mg/kg, i.p) 30 minutes and 0 minutes, respectively, before test start. The test compound was administered subcutaneously at a dose of 0.3, 1 or

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Abstract

L'invention concerne l'utilisation de composés capables d'inhiber l'activité de canaux potassiques activés par le calcium à faible conductance pour le traitement, la prévention ou l'atténuation de la maladie de Parkinson, ou pour contrôler le mouvement d'un patient atteint de la maladie de Parkinson.
PCT/DK2003/000678 2002-10-13 2003-10-09 Utilisation de medicaments bloquant les canaux skca pour lutter contre la maladie de parkinson WO2004035056A1 (fr)

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WO2006013210A3 (fr) * 2004-08-05 2006-05-04 Neurosearch As Nouveaux derives 2-amino benzimidazole et utilisation de ceux-ci comme modulateurs des canaux de potassium actives par calcium a faible conductance
US7482373B2 (en) 2002-05-13 2009-01-27 Icagen, Inc. Bis-benzimidazoles and related compounds as potassium channel modulators
US7482367B2 (en) 2005-08-30 2009-01-27 Novartis Vaccines And Diagnostics, Inc. Substituted benzimidazoles and methods of their use
WO2010015037A1 (fr) * 2008-08-08 2010-02-11 Howard Florey Institute Procédés et compositions thérapeutiques

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JAKOB WOLFART ET AL: "Selective Coupling of T-Type Calcium Channels to SK Potassium Channels Prevents Intrinsic Bursting in Dopaminergic Midbrain Neurons", THE JOURNAL OF NEUROSCIENCE, vol. 22, no. 9, 1 May 2002 (2002-05-01), pages 3404 - 3413, XP002268349 *
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7482373B2 (en) 2002-05-13 2009-01-27 Icagen, Inc. Bis-benzimidazoles and related compounds as potassium channel modulators
WO2006013210A3 (fr) * 2004-08-05 2006-05-04 Neurosearch As Nouveaux derives 2-amino benzimidazole et utilisation de ceux-ci comme modulateurs des canaux de potassium actives par calcium a faible conductance
US7737167B2 (en) 2004-08-05 2010-06-15 Neurosearch A/S 2-amino benzimidazole derivatives and their use as modulators of small-conductance calcium-activated potassium channels
US7482367B2 (en) 2005-08-30 2009-01-27 Novartis Vaccines And Diagnostics, Inc. Substituted benzimidazoles and methods of their use
US7732465B2 (en) 2005-08-30 2010-06-08 Novartis Vaccines And Diagnostics, Inc. Substituted benzimidazoles and methods of their use
US7767820B2 (en) 2005-08-30 2010-08-03 Novartis Vaccines And Diagnostics, Inc. Substituted benzimidazoles and methods of preparation
US8592459B2 (en) 2005-08-30 2013-11-26 Novartis Ag Substituted benzimidazoles and methods of their use
WO2010015037A1 (fr) * 2008-08-08 2010-02-11 Howard Florey Institute Procédés et compositions thérapeutiques

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