WO2004035056A1

WO2004035056A1 - Use of skca channel blocking drugs for combating parkinson's disease

Info

Publication number: WO2004035056A1
Application number: PCT/DK2003/000678
Authority: WO
Inventors: Karin Sandager Nielsen; Lene Teuber; Bo Skaaning Jensen
Original assignee: Neurosearch A/S
Priority date: 2002-10-13
Filing date: 2003-10-09
Publication date: 2004-04-29
Also published as: AU2003271548A1

Abstract

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.

Description

USE OF SK_Ca CHANNEL BLOCKING DRUGS FOR COMBATING PARKINSON'S DISEASE

TECHNICAL FIELD

BACKGROUND ART

Parkinson's disease (PD) 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. However, it has been shown that in patients suffering from PD the dopamine-containing neurons in the substantia nigra (SN) is degenerating, which part of the brain is critically involved in controlling movement.

Current treatment of PD consists of increasing the dopaminergic activity centrally by e.g. L-DOPA alone or in combination with dopamine agonists. Moreover, US 5677344 (Squibb & Sons) discloses a method for treating PD by administering an ATP-sensitive potassium channel blocking agent. However, the use of drugs acting on calcium-activated potassium channels has never been suggested.

Calcium-activated, voltage-independent K⁺ channels of small unitary conductance (SKca channels) are widely expressed in the central nervous system. The SKca channel family includes the SKc_a channel subunits SKι, SK₂ and SK₃. The distribution of S^ and SK₂ show a high degree of overlap and display the highest levels of expression in neocortical, limbic and hippocampal areas in the rat brain. In contrast, the SK₃ 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 SK₃>SK₂>SK-ι.

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, SK₂ and SK₃, 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 SK₃) 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 SK₃, in the treatment of bipolar disorder. No activity useful for combating PD is reported.

WO 97/48705 (University College London) discloses a particular group of chemical compounds useful as calcium activated potassium channel blocking agents. No activity useful for combating PD is reported.

US 5739127, US 5760230 and US 5874438 (Bayer AG) disclose another group of 4.4'-bridged bis-2,4-diaminoquinazoline derivatives acting on potassium channels. No activity useful for combating PD is reported.

WO 01/02406 (NeuroSearch) discloses cyclic bis-amino-quinazolines useful as potassium channel blocking agents. No activity useful for combating PD is reported.

Wolfart et al. [J. Neurosci., 2001 21(10):3443-56] describe that differential expression of SK3 is critical for pacemaker control in dopaminergic midbrain neurons.

Wolfart and Roeper [J. Neurosci., 2002 22(9): 3404- 13] describe that selective coupling of T-type calcium channels to SK potassium channels prevents intrinsic bursting in dopaminergic midbrain neurons.

SUMMARY OF THE INVENTION

It has now surprisingly been found that compounds capable of blocking the SKca channels, either unselectively or with selectivity towards SK₃, are able to relieve the symptoms of PD, and therefore are useful for combating PD.

Therefore, in its first aspect 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. Viewed from another aspect 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.

In a further aspect 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. Other objects of the invention will be apparent to the person skilled in the art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION

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.

According to the invention 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

Ca²⁺ activated potassium channel (SK_Ca channel). Preferred SKca blocking compounds of the invention are selective towards SKc_a channel subunit SK₃.

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 μM, or nanomolar range, i.e. of below 1 μM.

Particularly preferred 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).

In a further embodiment, 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. In a special embodiment, 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 μM, or nanomolar range, i.e. of below 1 μM. In a more preferred embodiment the SKca blocking compound for use according to the invention is a bridged or cyclic amino-imidazole derivative represented by Formula IA or IB,

or a bridged or cyclic amino-pyridine derivative represented by Formula MA or

MB,

or a bridged or cyclic amino-pyrimidine derivative represented by Formula

IMA or NIB,

or a bridged or cyclic amino-pyrimidine derivative represented by Formula

IVA, IVB or IVC,

or a pharmaceutically-acceptable addition salt thereof, in which formulas

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 R¹, R², R³ and R⁴, independently of each another, represent hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, haloalkyl, hydroxy, alkoxy, amino, nitro, cyano, phenyl, phenoxy or benzyl; or

R¹ and R² together, and/or R³ and R⁴ together, form a benzo-fused carbocyclic group, which benzo-fused carbocyclic group may optionally be substituted one or more times with substituents selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, haloalkyl, hydroxy, alkoxy, amino, nitro, cyano, phenyl, phenoxy or benzyl; and

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 Cι.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.

In another preferred embodiment the SKca blocking compound for use according to the invention is a bridged or cyclic amino-benzimidazole derivative represented by Formula VA or VB,

a bridged or cyclic amino-quinoline derivative represented by Formula VIA or

VIB,

or a bridged or cyclic amino-quinazoline derivative represented by Formula

VMA or VMB,

or a bridged or cyclic amino-quinazoline derivative represented by Formula

VIIIA, VIIIB or VIMC,

(VIIIA)

(VIIIB)

(VIIIC)

or a pharmaceutically-acceptable addition salt thereof, in which formulas

R⁵, R⁶, R⁷ and R⁸, 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.

In a third preferred embodiment A and B, independently of each another, represent a Cι-ι₀-methylene linker; or a -Co-₃-alkyl-"CYC"-Co-₃-alkyl- linker, wherein "CYC" represents a monocyclic saturated or unsaturated carbocyclic group. In a fourth preferred embodiment the C-i.-io-methylene linker is methylene, dimethylene; trimethylene; tetramethylene; pentamethylene; hexamethylene; octamethylene; or decamethylene.

In a fifth preferred embodiment the "CYC" represents a C₃. -cycloalkyl group or a phenyl group. In a sixth preferred embodiment the -C₀-₃-alkyl-"CYC"-C₀-3-alkyl- linker is (cis and/or trans)-1 ,3-cyclohexane-diyl, (cis and/or trans)-1 ,3-dimethylcyclohexane-α,α'- diyl, (cis and/or trans)-1 ,4-dimethylcyclohexane-α,α'-diyl, para-xylene-α.α'-diyl, meta- xylene-α,α'-diyl or 1 ,3-phenylene. In a seventh preferred embodiment 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.

In a most preferred embodiment the SKca blocking compound of Formula VA for use according to the invention is

or a pharmaceutically-acceptable addition salt thereof. In a most preferred embodiment the SKca blocking compound of Formula VIB for use according to the invention is

or a pharmaceutically-acceptable addition salt thereof. In a most preferred embodiment the SK_Ca blocking compound of Formula VIIIA for use according to the invention is

or a pharmaceutically-acceptable addition salt thereof. In a most preferred embodiment the SK_Ca blocking compound of Formula VII IB for use according to the invention is

or a pharmaceutically-acceptable addition salt thereof. Any combination of two or more of the embodiments described herein is considered within the scope of the present invention.

Definition of Substituents

In the context of this invention halogen represents a fluorine, a chlorine, a bromine or an iodine atom.

In the context of this invention 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 (Cι-₆-alkyl; lower alkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl. In a preferred embodiment alkyl represents a Chalky! group, including butyl, isobutyl, secondary butyl, and tertiary butyl. In another preferred embodiment of this invention alkyl represents a Cι.₃-alkyl group, which may in particular be methyl, ethyl, propyl or isopropyl.

In the context of this invention an alkenyl group designates a carbon chain containing one or more double bonds, including di-enes, tri-enes and poly-enes. In a preferred embodiment the alkenyl group of the invention comprises of from two to eight carbon atoms (C₂.₈-alkenyl), more preferred of from two to six carbon atoms (C₂- ₆-alkenyl), including at least one double bond. In a most preferred embodiment 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.

In the context of this invention an alkynyl group designates a carbon chain containing one or more triple bonds, including di-ynes, tri-ynes and poly-ynes. In a preferred embodiment the alkynyl group of the invention comprises of from two to eight carbon atoms (C₂-₈-alkynyl), more preferred of rom two to six carbon atoms (C₂-₆- alkynyl), including at least one triple bond. In its most preferred embodiment 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-octtetraynyl.

In the context of this invention a cycloalkyl group designates a cyclic alkyl group, preferably containing of from three to seven carbon atoms (C₃. -cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In the context of this invention 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.

In the context of this invention 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.

In the context of this invention an alkoxy group designates an "alkyl-O-" group, wherein alkyl is as defined above. Examples of preferred alkoxy groups of the invention include methoxy and ethoxy. In the context of this invention an amino group may be a primary (-NH₂), 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.

Pharmaceutically Acceptable Salts 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. Examples of 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 cinnamate derived from cinnamic acid, the citrate derived from citric acid, the em- bonate derived from embonic acid, the enantate derived from enanthic acid, the fuma- rate derived from fumaric acid, the glutamate derived from glutamic acid, the glycolate derived from glycolic acid, the lactate derived from lactic acid, the maleate derived from maleic acid, the malonate derived from malonic acid, the mandelate derived from mandelic acid, the methanesulphonate derived from methane sulphonic acid, the naphthalene-2-sulphonate derived from naphtalene-2-sulphonic acid, the phthalate derived from phthalic acid, the salicylate derived from salicylic acid, the sorbate derived from sorbic acid, the stearate derived from stearic acid, the succinate derived from succinic acid, the tartrate derived from tartaric acid, the toluene-p-sulphonate derived from p-toluene sulphonic acid, and the like. Such salts may be formed by proce- dures well known and described in the art.

Other acids such as 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. Examples of 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.

In the context of this invention the "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.

Steric Isomers

The chemical compounds of the present 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 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.

Methods of Preparation

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).

Pharmaceutical Compositions

In another aspect 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.

While 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.

In a preferred embodiment, 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. Pharmaceutical 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. Suitable examples of 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.

The chemical compound of the invention, together with a conventional adju- vant, 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 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. For preparing pharmaceutical compositions from a chemical compound of the present 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.

In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, 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. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture of fatty acid glyceride or cocoa butter, is first melted and 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. For example, 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. Alternatively, 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.

Also included are solid form preparations, intended for conversion shortly before use to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. In addition to the active component such preparations may comprise colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

For topical administration to the epidermis 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. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.

Alternatively 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). Conveniently 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.

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.

When desired, compositions adapted to give sustained release of the active ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. In such form, 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. Also, 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. 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. ED₅₀ and LD₅₀, 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 LD₅₀/ED₅₀. Pharmaceutical compositions exhibiting large therapeutic indexes are preferred.

The dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired, and the exact dosage should of course be determined by the practitioner. The actual dosage depend on the nature and severity of the disease being treated, and is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect. However, it is presently contemplated that pharmaceutical 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 μg/kg i.v. and 1 μg/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 μg/kg to about 10 mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

Methods of Therapy In another aspect 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.

In a more preferred embodiment a compound capable of selectively inhibiting the activity of a human small conductance calcium activated potassium channel subunit SK₃ is administered.

EXAMPLE

The invention is further illustrated with reference to the following example, which is not intended to be in any way limiting to the scope of the invention as claimed. Lesioning unilaterally the dopaminergic neurons projecting from the substantia nigra to the striatum by local injections of 6-Hydroxydopamine (6-OHDA) can be as used as an animal model of Parkinson's disease.

In these experiments 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 lesion is performed by unilaterally injecting 6-OHDA (2 μg/μL) using a Hamilton syringe with a flow-rate of approximately 0.5 μWΛ minute, and using the following stereotaxic coordinates: AP = -4.4, ML = -1.2, DV = -7.8, TB = -2.3.

In order to avoid postoperative pain 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

3 mg/kg 15 minutes before test start.

Each dose group consisted of 7-8 animals. A "Rotameter" measures the number of contralateral as well as ipsilateral rotations automatically.

The results of this experiment are presented in Table 1. Table 1

Number of Contralateral Rotations

p < 0.001 as compared to vehicle treatment.

These results show that pre-treatment with the test compound caused a dose-dependent increase in number of rotations contralaterally to the lesioned side, with 1 and 3 mg/kg significantly different from vehicle treatment (p < 0.001 , two way ANOVA with time-interval as dependent and treatment as independent factor).

Claims

A pharmaceutical composition 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.

Use of a compound capable of inhibiting the activity ("blocking") of a human small conductance calcium activated potassium channel (SKc_a channel) at a micomolar concentration (i.e. an SK_Ca 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 use according to claim 2, wherein the SK_Ca channel blocker is a selective towards the SKca channel subunit SK₃.

The use according to either of claims 2-3, wherein the SK_Ca channel blocker is a bridged or cyclic amino-imidazole derivative represented by Formula IA or IB,

or a bridged or cyclic amino-pyridine derivative represented by Formula IIA or MB,

or a bridged or cyclic amino-pyrimidine derivative represented by Formula IMA or 1MB,

or a bridged or cyclic amino-pyrimidine derivative represented by Formula IVA,

IVB or IVC,

or a pharmaceutically-acceptable addition salt thereof, in which formulas

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

R¹, R², R³ and R⁴, 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 Cι.-ιo-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 Cι-ι₀-methylene linker, and the remaining of R', R", R'", R"", R^*, R^**, R^*** and R^**** are as defined above.

The use according to claim 4, wherein the SK_Ca channel blocker is a bridged or cyclic amino-benzimidazole derivative represented by Formula VA or VB,

a bridged or cyclic amino-quinoline derivative represented by Formula VIA or VIB,

or a bridged or cyclic amino-quinazoline derivative represented by Formula VIIA or

VIIB,

or a bridged or cyclic amino-quinazoline derivative represented by Formula VIIIA, VIMB or VIMC, (VIIIA)

(VIIIC)

or a pharmaceutically-acceptable addition salt thereof, in which formulas

A, B, R', R", R'", R"", R^*, R^**, R^*** and R^**** are as defined above.

6. The use according to either of claims 4-5, wherein A and B, independently of each another, represent a Cι-ι₀-methylene linker; or a -Co-₃-alkyl-"CYC"-C₀-₃-alkyl- linker, wherein "CYC" represents a monocyclic saturated or unsaturated carbocyclic group.

7. The use according to claim 6, wherein the Ci.io-methylene linker is methylene, dimethylene; trimethylene; tetramethylene; pentamethylene; hexamethylene; octamethylene; or decamethylene.

8. The use according to claim 6, wherein "CYC" represents a C₃.₇-cycloalkyl group or a phenyl group.

9. The use according to claim 6, wherein the -C₀-₃-alkyl-"CYC"-C₀-₃-alkyl- linker is

(cis and/or trans)-1 ,3-cyclohexane-diyl, (cis and/or trans)-1 ,3-dimethyl- cyclohexane-α,α'-diyl, (cis and/or trans)-1 ,4-dimethylcyclohexane-α,α'-diyl, para- xylene-oc,α'-diyl, meta-xylene-α,α'-diyl or 1 ,3-phenylene. 5

10. The use according to any of claims 4-9, wherein 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.

10 11. The use according to claim 5, wherein the SK_Ca channel blocker of Formula VA is

or a pharmaceutically-acceptable addition salt thereof.

15 12. The use according to claim 5, wherein the SK_Ca channel blocker of Formula VIB is

or a pharmaceutically-acceptable addition salt thereof.

20 13. The use according to claim 5, wherein the SK_Ca channel blocker of Formula VIIIA is

or a pharmaceutically-acceptable addition salt thereof.

14. The use according to claim 5, wherein the SK_Ca channel blocker of Formula VIIIB is

or a pharmaceutically-acceptable addition salt thereof.

15. 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 (SKc_a channel) at a micomolar concentration (i.e. an SK_Ca channel blocker), or a pharmaceutically-acceptable addition salt thereof.

6. The method of claim 15, wherein a compound capable of selectively inhibiting the activity of a human small conductance calcium activated potassium channel subunit SK₃ is administered.