FIELD OF THE INVENTION The present invention relates to compounds of formula (I) which are potassium channel inhibitors. Compounds in this class may be useful as KvI.3 inhibitors for immunomodulation and the treatment of autoimmune, chronic inflammatory, metabolic diseases and the like. Pharmaceutical compositions comprising the compounds and their use in the treatment of autoimmune and inflammatory diseases and in the treatment of arrhythmia are also provided.

BACKGROUND

Ion channels are proteins that span the lipid bilayer of the cell membrane and provide an aqueous pathway through which specific ions such as Na ⁺ , K ⁺ , Ca ²⁺ and Cl ^" can pass (Herbert, 1998). Potassium channels represent the largest and most diverse sub-group of ion channels and they play a central role in regulating the membrane potential and controlling cellular excitability (Armstrong & Hille, 1998). Potassium channels have been categorized into gene families based on their amino acid sequence and their biophysical properties (for nomenclature see Gutman et ah, 2003).

Compounds which modulate potassium channels have multiple therapeutic applications in several disease areas including autoimmune, inflammatory, cardiovascular, neuronal, auditory, renal and metabolic mediated diseases (Shieh et ah, 2000; Ford et ah, 2002, Xie et al, 2004). The potassium channel KvI.3 is found in a number of tissues including neurons, blood cells, osteoclasts, macrophages, epithelia, and T- and B-lymphocytes. Furthermore, KvI.3 inhibition has been shown to modulate T-cell function which has implications in many autoimmune diseases including psoriasis, rheumatoid arthritis, multiple sclerosis, obesity, diabetes and inflammatory bowel disease (Beeton et ah, 2006). KvI .3 Channel Blockers for Autoimmune Disorders

The role of autoreactive, late-stage, memory T _EM cells in the pathogenesis of a variety of autoimmune diseases including psoriasis, rheumatoid arthritis, multiple sclerosis, IBD and others is well established. Activation of T _EM cells is followed by substantial up- regulation of KvI.3 channel expression and, as a result, KvI.3 becomes the predominant route of potassium efflux from the cell. Thus, selective blockade of KvI.3 causes membrane depolarisation and inhibition of Ca ²⁺ influx, leading to inhibition of cytokine production and cell proliferation and function. Kv 1.3 thus represents a novel therapeutic target of great interest for autoimmune disease control.

T-cells and Autoimmunity

T-cells are lymphocytes which play a central role in cell mediated immunity. One of the major forms of T-cell is the helper T-cell (T _H ), also known as CD4+ cells which plays an essential role in the development of autoimmune diseases. Through the production of the cytokine interleukm 2 (IL-2), CD4+ T-cells can create the second main type of T cell known as cytotoxic T-cells (CD8+). Naϊve (inactive) CD4+ and CD8+ T-cells express both proteins (CCR7+CD45RA+) and use the chemokine receptor CCR7 as a key to gain entry into lymph nodes. Within lymph nodes, the naϊve T-cells encounter antigen and through an activation process, change into "effector" T-cells that produce cytokines and proliferate. Once the ensuing immune response subsides, most naϊve effectors die, but a few differentiate into long-lived central memory cells (T _CM )- T _C M cells, like naϊve cells, use CCR.7 to home to the lymph nodes to encounter their cognate antigen. Upon antigenic stimulation, T _C M cells change into "T _CM effector" cells that produce cytokines and proliferate. They too suffer the same fate as naϊve effectors, the majority dying after the immune response wanes, leaving a few long-lived survivors for further challenge. Repeated antigenic challenge, as might happen in autoimmune diseases or in chronic infections, causes T _CM cells to differentiate into short-lived "effector memory T-cells" (TE _M ) that lack expression of both CCR7 and CD45RA, and do not need to home to lymph nodes for antigen-induced activation. A subset of CD8+ TEM cells reacquire CD45RA and become CCR7-CD45RA+ T _EM RA cells. Upon activation, both CD4+ and CD8+ T _EM cells change into T _EM effectors that migrate rapidly to sites of inflammation and produce large amounts of the proinflammatory cytokines, interferon-γ (IFN-γ) and tumor necrosis factor α (TNFα). In addition, CD8+ T _EM effectors carry large amounts of perforin and are therefore immensely destructive (Wulff et al, 2003, Beeton et al, 2005).

Functional Role of Kv 1.3 in T-cells and Autoimmune Disorders

Human T-cells express two K ⁺ channels, Kv 1.3 and IKCaI, that provide the counterbalance cation efflux necessary for the sustained elevation of cytosolic Ca ²⁺ levels required for gene transcription, proliferation and cytokine secretion (Panyi et al, 2004, Chandy et al, 2004). The KvI.3 and IKCaI (also known as KCa3.1) channels regulate membrane potential and facilitate Ca ²⁺ signalling in T-lymphocytes. KvI.3 opens in response to membrane depolarisation and maintains the resting membrane potential (initiation phase), whereas IKCaI opens in response to an increase in cytosolic Ca ²⁺ and hyperpolarises the membrane potential (Beeton et al, 2001). Selective blockade of K ⁺ channels leads to membrane depolarisation, which in turn inhibits Ca ⁺ influx and shuts down cytokine production and cell proliferation. Early in vitro studies, using channel blocker toxins, clearly demonstrate that Kv 1.3 channels are essential for the synthesis (gene activation) and secretion of the cytokine IL-2 after T-cell activation (Price et al, 1989) and provide a rationale for the potential therapeutic use of inhibitors of this channel in immunological disorders. The role of autoreactive T-cells in the pathogenesis of autoimmune diseases has clearly been demonstrated in animal models. Disease-specific, autoreactive T-cells in several other autoimmune diseases are also reported to exhibit a memory phenotype. Autoreactive T _EM cells are also implicated in psoriasis, rheumatoid arthritis, multiple sclerosis, BBD, vitiligo, uveitis, pemphigus, inflammatory myopathies, Hashimito disease, and scleroderma (Beeton et al, 2005). "Late" memory T- and B-cells have been implicated in the disease progression and tissue damage in a number of autoimmune diseases, in transplant rejection and chronic graft- versus-host disease. Modulators of the Kv 1.3 channel may allow selective targeting of disease-inducing effector memory T-cells and memory B-cells without compromising the normal immune response and as a result are likely to have a preferred side-affect profile than agents that bring about more general immunosuppression. The observation that the Kv 1.3 blocker margatoxin (MgTX) effectively suppressed the delayed-type hypersensitivity (DTH) response in vivo was provided by Koo et al, 1999. In addition MgTX was also shown to inhibit primary antibody response in non-sensitised animals (secondary antibody response was not affected by MgTX. These latter results are in agreement with the notion that KvI.3 channels are predominant in resting T lymphocytes and regulate their function, while IKCaI channels are more important in pre-activated T lymphocytes. Correolide (Koo et al, 1999) and PAP-I (Schmitz et al, 2005) are novel immunosuppressants which block KvI.3 channels and are effective in the DTH model. Because the cellular components involved in DTH response are similar to those found in autoimmune diseases and allograft rejection, the results obtained are very promising for the development of Kv 1.3 channel blockers as new immunosuppressants.

In the early 1980's a number of compounds were reported to block Kv 1.3 channels at micromolar to millimolar concentrations as described by Triggle et al, in "Voltage Gated Ion Channels as Drug Targets" these include classical Kv channel inhibitors such as 4- aminopyridine and tetramethylammonium, and other non specific compounds such as the calcium activated potassium channel blockers quinine and ceteidil, the phenothiazine antipscychotics chloropromazine and trifluoroperazine, the classical calcium channel inhibitors verapamil, diltiazem, nifedipine and nitrendipine, and the beta blocker propranolol.

Also in the 1980's natural products extracted from scorpions, snakes and other marine organisms were found to be potent inhibitors of KvI.3 channels, these were primarily short peptides (<70 residues) that are stabilised by multiple sulfide bonds. The first of these potent inhibitors was isolated from the venom of the scorpion Leiurus quinquestriatus hebraeus and was named charybdotoxin (ChTX) (Sands et al, 1989), there after screening of other scorpion venoms led to the identification of more potent Kv 1.3 blocking toxins, these include margatoxin (MgTX) (Garcia et al, 1993), agitoxin- 2 (Garcia et al, 1994), hongotoxin (Koshchak et al, 1998 ), pandinus imperator toxin 2 (Pi2) (Peter et al, 2001) and orthochirus scrobiculosus (OSKl) (Mouhat et al, 2005) among others. With the exception of OSKl (300 fold selective over the nearest related channel) none of the scorpion toxins were selective for Kv 1.3

One of the most potent and selective KvI.3 blockers to date, which was extracted from sea anemone is stichodactyla helianthus toxin (Shk) (Pennington et al, 1996) this has been reported for the treatment of autoimmune disease through the blockade of KvI.3 (US 6,077,680). Shk and its synthetic derivative Shk-Dap ²² with improved selectivity profile display pico molar activity (Pennington et al, 1998) however, these peptides proved to have unfavourable properties for further development.

Recently more novel and selective small molecule KvI.3 channel blockers have been reported for the management of autoimmune disorders. These include the iminodihydroquinolines WIN173173 and CP339818 (Nguyen et al, 1996), the benzhydryl piperidine UK-78,282 (Hanson et al 1999), correolide (Felix et al, 1999), cyclohexyl-substituted benzamide PAC (US-06194458, WO0025774), sulfamidebenzamidoindane (US-06083986), Khellinone (Baell et al, 2004), dichloropenylpyrazolopyrimidine (WO-OO 140231) and psoralens (Wulff et al, 1998., Vennekamp et al, 2004, Schmitz et al, 2005).

Sulfonamides have been reported to be useful as inhibitors of 11-beta-hydroxysteroid dehydrogenase typel, CCR5, H3 receptor and mitotic kinesins amongst others.

1,4-substituted aryl tertiary sulfonamides, wherein position 4 is substituted with an amide have been claimed as inhibitors of 11-betahydroxysteroid dehydrogenase typel, for the treatment and prevention of hyperglycemia in diseases such as type-2 diabetes (WO2004065351).

1,4-substituted aryl tertiary sulfonamides, wherein position 4 is optionally substituted with substituted alky, alkoxyamino, sulfonyl, acyl, alkoxy carbonyl or aminocarbonyl have been claimed as inhibitors of mitotic kinesins as effective anti cancer agents (WO2007056078). 1,4-substituted aryl tertiary sulfonamides, wherein the sulfonamide N is linked to lower alkyl, lower alkenyl, cycloalkyl or cycloalkyl and position 4 is optionally substituted with carbonyl, alkyl or secondary alcohol have been claimed as class III antiarrythmics (US4876262).

1,4-substituted aryl tertiary sulfonamides, wherein position 4 is optionally substituted with alkyl, carbonyl or sulfmyl group have been claimed as inhibitors of CCR5 for the treatment of HIV infection and other CCR5 mediated disorders (WO2000454974).

1,4-substituted aryl tertiary sulfonamides have been claimed as herbicides (WO200690792).

1,4-substituted aryl tertiary sulfonamides, wherein position 4 is substituted with an amide have been claimed as inhibitors of histamine H3 receptor for the treatment of obesity, cognitive deficiencies, narcolepsy and other H3 receptor related diseases (WO200756078)

1,4-aryl tertiary methylsulfonamides, wherein position 4 is substituted with cyclic amides and the sulfonamide N is linked to methylnaphthalene have been reported to be potent inhibitors of Factor Xa and show strong anti-thrombotic effects (Wenrong et al, 2003)

1,4-substituted aryl tertiary phenylsulfonamides, wherein position 4 is substituted with a secondary alcohol are reported to inhibit the human pregnane receptor (PXR) which plays a key role in the regulation of regulation of metabolism and excretion of potentially harmful compounds. This is desirable as a potential way to control up-regulation of drug metabolism pathways during the therapeutic treatment of disease ( Xue et al, 2007)

It has now surprisingly been found that compounds of general formula (I) set out below act as inhibitors of potassium channels. These compounds are particularly useful for inhibiting the potassium channel Kv 1.3 and treating diseases associated with the inhibition of the potassium channel Kv 1.3. This invention is not limited to treating diseases mediated by KvI.3, the compounds also being useful to treat other diseases which require potassium channel inhibition (Triggle et α/,2006). Thus, in a first aspect, the present invention provides a compound of formula (I)

or its salts or pharmaceutically acceptable derivatives wherein;

R ₁ is selected from the group consisting of optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl and optionally substituted heteroaryl;

R ₂ is selected from the group consisting of optionally substituted acyl, optionally substituted sulfonyl and optionally substituted sulfamoyl;

R ₃ is selected from the group consisting of hydrogen, halogen, hydroxyl, alkoxy, aryloxy, optionally substituted alkyl, optionally substituted amino, optionally substituted amino carbonyl, optionally substituted amino sulfonyl or nitrile;

X ₁ is selected from a group consisting of a chemical bond, CR ₇ R ₈ , C(=O), C(=NH), NRg,

NHC(=O), and SO ₂ wherein;

R ₇ and R ₈ are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl or;

R ₇ and R ₈ together form an optionally substituted C _4-6 cycloalkyl ring;

R ₉ is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl and optionally substituted heteroaryl; A represents an optionally substituted saturated or partially saturated 4-7 membered ring with the general formula:

or is selected from:

For each occurrence; X ₂ is CH or N; X ₃ is C(R ₅ ) ₂ , N(R _5b ), O or S;

X ₄ is independently selected from CO=O), or C(R ₄ ) ₂ ;

R ₄ for each occurrence is independently hydrogen, halogen, optionally substituted amino, hydroxyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl;

R ₅ for each occurrence is independently hydrogen, halogen, optionally substituted amino, hydroxyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted alkanoyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl;

Rs _b is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl; and n = 1 or 2.

As used herein, the following definitions shall apply unless otherwise indicated. The term "optionally substituted" means that a group may be substituted by one or more substituents which may be the same or different. When otherwise not specified, these substituents are selected from alkyl, cycloalkyl, -O-C(halogen) ₃ preferably -OCF ₃ , biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl, carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulfamoyl, sulfonyl, sulfinyl, sulfenyl, sulfonamido or urea.

The term "alkyl group" as used herein, is typically a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, preferably 2, 3, 4, or 5 carbon atoms such as a C _1-4 alkyl group or moiety, for example methyl, ethyl, n-propyl, z-propyl, butyl, z-butyl and t-butyl. An alkyl group or moiety may be unsubstituted or substituted at any position.

Typically, it is unsubstituted or carries one, two or three substituents. Suitable substituents include cyano, halogen, hydroxyl, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro, aryl and heteroaryl. The alkyl moiety may also be an "unsaturated alkyl" moiety, which means that it contains at least one alkene or alkyne moiety. An "alkene" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond. An "alkyne" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.

The term "cycloalkyl" as used herein refers to mono- or bicyclic ring or ring systems consisting of 3 to 11 carbon atoms i.e. 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms. The ring system may be a "saturated ring", which means that the ring does not contain any alkene or alkyne moieties. The cycloalkyl group may also be an "unsaturated ring" which means that it contains at least one alkene or alkyne moiety and provided that the ring system is not aromatic. The cycloalkyl group may be unsubstituted or substituted as defined herein. In addition to the above mentioned substituents one or more ring carbon atoms may also be bonded via a double bond to a group selected from NH, S and O. The cycloalkyl substituent may be bonded via a linker group such as a C _1-6 alkyl group, except where the optional substituent is alkyl. One or more hydrogens of the alkyl group in the linker may be replaced by a moiety selected from the group consisting of hydroxy, halo, cyano, amino, thiol, C _1-6 alkoxy, Cμβalkylthio, C _1-6 alkylamino and Ci-βdialkylamino.

The term "aryl group" as used herein, is typically a C _6- I ₀ aryl group such as phenyl or naphthyl. A preferred aryl group is phenyl. An aryl group may be unsubstiruted or substituted at any position. Typically, it carries 1, 2, 3 or 4 substituents. Suitable substituents include cyano, halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido, MV- dialkylamino, sulfonamido, aryl and heteroaryl.

The term "carbocyclic" refers to a compound which contains one or more covalently closed ring structures and the atoms forming the backbone of the ring(s) are all carbon atoms. The term thus distinguishes carbocyclic from heterocyclic rings. Carbocyclic groups include both, a "cycloalkyl group", which means a non-aromatic carbocycle, and a "carbocyclic aryl" group, which means an aromatic carbocycle. The carbocyclic group may optionally be substituted as defined herein.

The term "heterocyclic" or "heterocyclo" as used herein refers to mono- or bicyclic rings or ring systems which include one or more heteroatoms selected from Ν, S and O. The rings or ring systems include 1 to 6 carbon atoms in addition to the heteroatom(s) i.e. 1, 2, 3, 4, 5,or 6 carbon atoms. The term heterocyclic group includes both, a "heteroalicyclic" group, which means a non-aromatic heterocycle and a "heteroaryl" group, which means an aromatic heterocycle. The heterocyclic moiety may be unsubstiruted or substituted as defined herein and the substituents, when positioned adjacent to one another, may combine to form cycloalkyl or heteroalicyclic ring systems for example methylendioxy or difiuoromethylendioxy. The heterocyclic substituent may be bonded via a carbon atom or a heteroatom. The heterocyclic group may also include the oxides of nitrogen and sulfur if nitrogen or sulfur are present in the ring.

The term "heteroaryl" as used herein refers to mono- or bicyclic rings or ring systems which include one or more heteroatoms selected from Ν, S and O. The rings or ring systems include 3 to 13 carbon atoms, i.e. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms in addition to the heteroatom(s) and contain at least one aromatic ring with a heteroatom. The heteroaryl group may also include the oxides of nitrogen and sulfur if nitrogen or sulfur is present, or an oxo-group respectively. Examples of monocyclic heteroaryl groups include but are not limited to furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl. Examples of bicyclic heterocycles include but are not limited to indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl and the like. Examples of tricyclic heterocycles include but are not limited to thianthrenyl, xanthenyl, phenoxathiinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl. The heteroaryl group may be unsubstituted or substituted as defined herein. The substituents, when positioned adjacent to one another, may combine to form a cycloalkyl or heteroalicyclic ring for example methylendioxy and difluoromethylendioxy. The heteroaryl substituent may be bonded via a carbon atom or a heteroatom.

The term "arylalkyl", as used herein, refers to a chemical moiety of formula aryl-C _1-6 alkyl or Ci _-6 alkyl- aryl as those terms are defined herein.

The term "heteroarylalkyl", used as herein, refers to a chemical moiety of formula heteroaryl-C _1-6 alkyl or C _1-6 alkyl- heteroaryl as those terms are defined herein.

The term "acyl", as used herein, refers to a chemical moiety of formula (CH ₂ )yC(=O)Rz wherein y is 1-6, i.e 1, 2, 3, 4, 5, or 6.

The term "amidino" refers to a chemical moiety with the formula (CH ₂ )yC(=NH)NRzR'z wherein y is 1-6, i.e 1, 2, 3, 4, 5, or 6. The term "amido" refers to both, a "C-amido" group which means a chemical moiety with the formula -C(=O)NRzR'z and a "iV-amido" group which means a chemical moiety with the formula -NRzC(=O)R'z.

The term "amine" or "amino" refers to a chemical moiety of formula -NRzR' z. The definition of an amine is also understood to include their JV-oxides.

A "cyano" group refers to a chemical moiety of formula -CN.

The term "hydroxy" or "hydroxyl" as used herein, refers to a chemical moiety of formula -OH.

The term "halogen" or "halo" refers to an atom selected from the group consisting of fluorine, chlorine, bromine and iodine.

The term "alkanoyl", as used herein, refers to a chemical moiety with the formula -C(=O)Rz.

The term "sulfone" or "sulfonyl" refers to a chemical moiety with the formula -S(=O) ₂ Rz.

The term "sulfinyl" refers to a chemical moiety with the formula -S(=O)Rz.

The term "sulfenyl" refers to a chemical moiety with the formula -SRz.

A "sulfamoyl" group refers to a chemical moiety with the formula -N-S(=O) ₂ NRzR'z.

The term "sulfonamido" refers to both an "S-sulfonamido" group which means a chemical moiety with the formula -S(=0) ₂ NRzR'z and an "iV-sulfonamido" group which means a chemical moiety with the formula -N-S(=O) ₂ R'z. The term "thiocarbonyl" refers to a chemical moiety with the formula (CH ₂ )yC(=S)Rz wherein y is 1-6, i.e 1, 2, 3, 4, 5, or 6.

The term "thio" or "thiol", as used herein, refers to a chemical moiety of formula -SH.

The term "thioamide" refers to both a "C-thioamido" group which means a chemical moiety with the formula (CH ₂ )yC(-S)NRzR'z and a 'W-thioamido" group which means a chemical moiety with the formula (CH ₂ )yNRzC(=S)R'z wherein y is 1-6, i.e 1, 2, 3, 4, 5, or 6.

An "urea" group refers to a chemical moiety of formula -NRzC(=O)NRzR'z.

Rz and R'z are independently selected from the group consisting of hydrogen, Ci _-6 alkyl, cycloalkyl, C _1-6 alkoxy, aryl-C _1-6 alkyl, aryl and heteroaryl.

One preferred embodiment relates to compounds where A is selected from-

Wherein; n = 1 or 2

X ₃ is C(Rs) ₂ , N(R _5b ), or O;

X ₄ is independently selected from C(=O), or C(R ₄ ) ₂

R ₄ for each occurrence independently represents hydrogen, halogen, hydroxyl, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl;

R ₅ for each occurrence independently represents hydrogen, halogen, optionally substituted amino, hydroxyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted alkanoyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl;

R _5b represents hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl.

Preferably R ₂ is selected from a group consisting of C(=0)Rio, SO ₂ R ₁₀ wherein; R ₁₀ is selected from NR ₁₁ R ₁₂ , optionally substituted aryl, and optionally substituted heteroaryl. More preferably Rio is selected from; NRnR ₁₂ or formula (II), (III), (IV) or (V)

(H) (III) (IV) (V)

Wherein;

Rn and Ri ₂ are the same or different and each represents hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl;

G, J, L, D, and E are the same or different and each represents C, or N with the proviso that in each instance at least one of G, J, L, D, or E is N;

Where Rio is formula (II), L may also represent O or S and

Where Ri ₀ is formula (III), G may also represent O or S; Ri ₃ and Ri ₄ are the same or different and each represents hydrogen, halogen, hydroxyl, optionally substituted Ci _-3 alkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl or may be taken together to form an optionally substituted saturated or partially saturated 5-7 membered heterocyclic or carbocyclic ring; Ri ₅ , Ri ₆ , Ri7, Ri8 _> and R ₁ Q are the same or different and each represents hydrogen, halogen, hydroxyl, optionally substituted amino, nitrile, optionally substituted Ci _>3 alkyl, any of the pairs Ri ₅ and Ri ₆ , or R ₁₆ and R ₁₇ , or Rn and R ₁₈ , or Ri ₈ and R\g or may be taken together to form an optionally substituted saturated or partially saturated 5-7 membered heterocyclic or carbocyclic ring;

Ri is selected from optionally substituted arylalkyl, and optionally substituted heteroarylalkyl. More preferably Rj is selected from formula (VI)

Wherein;

R20, R21, R22, R23 and R ₂₄ are the same or different and each represents hydrogen, halogen, hydroxyl, optionally substituted amino, nitrile, optionally substituted Ci _-3 alkyl or optionally substituted alkoxy;

R ₂ 5 and R ₂₆ are the same or different and each represents hydrogen, hydroxyl, and optionally substituted Ci _-3 alkyl

R ³ is selected from the group consisting of hydrogen, halogen, hydroxyl, nitrile, or optionally substituted alkyl , preferably hydrogen, halogen or optionally substituted alkyl.

Xi is preferably selected from a group consisting of a chemical bond, CH ₂ , and C(=O).

The most preferred compounds of the invention are those of formula (VII):

Wherein; n = 1 or 2

X ₁ is selected from a group consisting of a chemical bond, CH ₂ , C(=O) X ₃ is C(Rs) ₂ , N(R _5b ), orO X ₄ is CC=O) ₅ Or C(R ₄ ) ₂ R ₃ is selected from the group consisting of hydrogen, halogen, hydroxyl or optionally substituted C _1-3 alkyl

R ₄ for each occurrence independently represents hydrogen, halogen, hydroxyl, optionally substituted aryloxy, optionally substituted C _1-3 alkyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl. Preferably R ₄ for each occurrence independently represents fluoro, optionally substituted methyl, hydroxyl, trifluoromethyl, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted benzyloxy or optionally substituted oxadiazole. R ₅ for each occurrence independently represents hydrogen, halogen, optionally substituted amino, hydroxyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted alkanoyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl. Preferably R ₅ for each occurrence independently represents fluoro, methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, isobutyl, /ert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted phenethyl, hydroxyl, substituted hydroxyethyl, hydroxypropyl, hydroxybutyl, optionally substituted phenoxy, optionally substituted benzyloxy, methoxyethyl, methoxypropyl, phenoxyethyl, benzyloxyethyl, acetyl, propionyl, substituted benzoyl, phenacyl, imidazoyl, pyrazoyl, pyridinoyl, oxadiazoloyl, thiazoloyl, acetamide, methylacetamide, dimethylacetamide, ethylacetamide, diethylacetamide, tøt-butylacetamide, pyridylacetamide, cyclopropylacetamide, cyclobutylacetamide, cyclopentylacetamide, or cyclohexylacetamide. More preferably R ₅ for each occurrence independently represents fluoro, optionally substituted methyl, hydroxyl, optionally substituted cyclohexyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted phenoxy, optionally substituted benzyloxy, or thiazoloyl. R _5b represents hydrogen, optionally substituted Ci _-3 alkyl, optionally substituted phenyl and optionally substituted heteroaryl.

R ₁₀ is selected from; NRi iRi2 or a compound of formula (II), (III), (IV) or (V)

(H) (III) (IV) (V)

Wherein;

Rn and R ₁₂ are the same or different and each represent optionally substituted C ₁ ^ alkyl.

Preferably Rn and Rj ₂ are alkyl, preferably CH ₃ ; G, J, L, D, and E are the same or different and each represents C, or N with the proviso that in each instance at least one of G, J, L, D, or E is N;

Where when Rio is formula (II), L may also represent O or S and

Where when Rio is formula (III), G may also represent O or S

Ri ₃ and R ₁₄ are the same or different and each represents hydrogen, halogen, hydroxyl, optionally substituted Ci _-3 alkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl or may be taken together to form an optionally substituted saturated or partially saturated 5-7 membered heterocyclic or carbocyclic ring. Preferably, Rj ₃ and Rj ₄ are independently alkyl, preferably CH ₃ .

Ri ₅ , Ri ₆ , Ri ₇ , Ri ₈ , and R ₁₉ are the same or different and each represents hydrogen, halogen, hydroxyl, optionally substituted amino, nitrile, optionally substituted C _1-3 alkyl, any of the pairs R ₁₅ and Ri ₆ , or Rj ₆ and Ri ₇ , or R ₁₇ and Rj ₈ , or Rj ₈ and R] ₉ may be taken together to form an optionally substituted saturated or partially saturated 5-7 membered heterocyclic or carbocyclic ring

Preferably R ₁₀ is substituted imidazole, substituted pyrazole, substituted pyrrole, substituted substituted oxazole, substituted oxadiazole, substituted thiazole, substituted thiadiazole, substituted pyridine, substituted pyrimidine, substituted pyrazine, substituted pyridazine, substituted triazine, optionally substituted phenyl, tetrahydrobenzofuran, benzopyran, dihydrobenzodioxin, benzoxazinone, benzooxadiazole, benzodioxole, indoline, indole, indazole, or benzomorpholine. Most preferably R ₁₀ is substituted imidazole, substituted pyrazole, substituted pyridine, phenyl, fluorophenyl, cyanophenyl, tetrahydrobenzofuran, benzopyran, dihydrobenzodioxin, benzoxazinone, benzooxadiazole, benzodioxole, indoline, or benzomorpholine;

R-2Q R_u R ₂ 2, R23 and R ₂₄ are the same or different and each represents hydrogen, halogen, hydroxyl, optionally substituted amino, nitrile, optionally substituted C _1-3 alkyl or optionally substituted alkoxy. Preferably R ₂ o R ₂ 1 R22, R23 and R ₂₄ are independently selected from hydrogen, fluoro, chloro or methyl.

Particularly preferred compounds of the invention include:

N-(4-Chloro-benzyl)-N-[4-(4-phenyl-piperazine-l-carbonyl) -phenyl]- benzenesulfonamide;

N-Benzyl-N-[4-(4-phenyl-piperazine-l-carbonyl)-phenyl]-be nzenesulfonamide;

N-(2-Chloro-benzyl)-7V-[4-(4-phenyl-piperazine-l-carbonyl )-phenyl]- benzenesulfonamide; iV-(3-ChloiO-benzyl)-N-[4-(4-phenyl-piperazine- 1 -carbonyl)-phenyl] - benzenesulfonamide;

N-(4-Fluoro-benzyl)-JV-[4-(4-phenyl-piperazine-l-carbonyl )-phenyl]- benzenesulfonamide;

Νaphthalene-2-sulfonic acidbenzyl-[4-(4-phenyl-piperazine-l-carbonyl)-ρhenyl]-amid e; iV-Benzyl-3,4-dimethoxy-N-[4-(4-ρhenyl-piperazine-l-carbony l)-phenyl]- benzenesulfonamide;

2,3-Dihydro-benzo[l ,4]dioxine-6-sulfonic acid benzyl-[4-(4-phenyl-piperazine-l- carbonyl)-phenyl]-amide; iV-Benzyl-4-methyl-7V-[4-(4-phenyl-piperazine-l-carbonyl)-ph enyl]-benzenesulfonamide;

Thiophene-2-sulfonic acid benzyl-[4-(4-phenyl-piperazine- 1 -carbonyl)-phenyl]-amide; Thiophene-3 -sulfonic acid benzyl-[4-(4-phenyl-piperazine-l-carbonyl)-phenyl]-amide;

N-Benzyl-4-fluoro-N-[4-(4-phenyl-piperazine-l-carbonyl)-p henyl]-benzenesulfonamide; N-Benzyl-2-fluoro-iV-[4-(4-phenyl-piperazine-l-carbonyl)-phe nyl]-benzenesulfonamide;

N-Benzyl-3-fluoro-N-[4-(4-phenyl-piperazine-l-carbonyl)-p henyl]-benzenesulfonamide;

N-Benzyl-4-cyano-N-[4-(4-phenyl-piperazine-l-carbonyl)-ph enyl]-benzenesulfonamide;

N-Benzyl-3-cyano-N-[4-(4-phenyl-piperazine-l-carbonyl)-ph enyl]-benzenesulfonamide; N-Benzyl-2-cyano-iV-[4-(4-phenyl-piperazine-l-carbonyl)-phen yl]-benzenesulfonamide;

1 -Methyl- lH-imidazole-4-sulfonic acid benzyl-[4-(4-phenyl-piperazine- 1 -carbonyl)- phenyl] -amide;

N-Benzyl-2-methyl-N-[4-(4-phenyl-piperazine-l-carbonyl)-p henyl]-benzenesulfonamide;

N-Benzyl-3-methyl-N-[4-(4-phenyl-piperazine-l-carbonyl)-p henyl]-benzenesulfonamide; N-Benzyl-3-methoxy-N-[4-(4-phenyl-piperazine-l-carbonyl)-phe nyl]- benzenesulfonamide;

N-B enzyl-3 , 5 -dichloro-N- [4-(4-phenyl-piperazine- 1 -carbonyl)-phenyl] - benzenesulfonamide;

N-Benzyl-3-chloro-N-[4-(4-phenyl-piperazine-l-carbonyl)-p henyl]-benzenesulfonamide; N-(3-Fluoro-benzyl)-N-[4-(4-phenyl-piperazine-l-carbonyl)-ph enyl]- benzenesulfonamide;

N-(2-Methoxy-benzyl)-N-[4-(4-phenyl-piperazine-l-carbonyl )-phenyl]- benzenesulfonamide;

N-(3-Methoxy-benzyl)-N-[4-(4-phenyl-piperazine-l-carbonyl )-phenyl]- benzenesulfonamide;

N-(2-Methyl-benzyl)-N-[4-(4-phenyl-piperazine-l-carbonyl) -phenyl]- benzenesulfonamide;

N-(4-Methyl-benzyl)-N-[4-(4-phenyl-piperazine-l-carbonyl) -phenyl]- benzenesulfonamide; N-[4-(4-Phenyl-piperazine-l-carbonyl)-phenyl]-N-(4-trifluoro methyl-benzyl)- benzenesulfonamide;

N-[4-(4-Phenyl-piperazine-l-carbonyl)-phenyl]-N-(3-triflu oromethoxy-benzyl)- benzenesulfonamide;

N-(2-Cyano-benzyl)-N-[4-(4-phenyl-piperazine-l-carbonyl)- phenyl]- benzenesulfonamide; N-(4-Cyano-benzyl)-N-[4-(4-phenyl-piperazine-l-carbonyl)-phe nyl]- benzenesulfonamide;

2,2-Dimethyl-chroma«-6-sulfonic acid benzyl-[4-(4-phenyl-piperazine- 1 -carbonyl)- phenyl]-amide; N-Benzyl-4-nitro-N-[4-(4-phenyl-piperazine-l-carbonyl)-pheny l]-benzenesulfonamide;

Furarc-2-sulfonic acid benzyl-[4-(4-phenyl-piperazine- 1 -carbonyl)-phenyl]-amide; iV-Benzyl-N-[3-methyl-4-(4-phenyl-piperazine-l-carbonyl)-phe nyl]-benzenesulfonamide;

N-Benzyl-N-[2-fluoro-4-(4-phenyl-piperazine-l-carbonyl)-p henyl]-benzenesulfonamide; iV-Benzyl-N-[3-methoxy-4-(4-phenyl-piperazine-l-carbonyl)-ph enyl]- benzenesulfonamide;

N-Benzyl-N-[4-(3,4-dihydro-lH-isoquinoline-2-carbonyl)-pl ienyl]-benzenesulfonamide; iV-Benzyl-N-[4-(2,6-dimethyl-morpholine-4-carbonyl)-phenyl]- benzenesulfonamide;

Λ/-Benzyl-N-[4-(piperidine-l-carbonyl)-phenyl]-benzenesu lfonamide; iV'Benzyl-4-ethyl-N-[4-(4-phenyl-piperazine-l-carbonyl)-phen yl]-benzenesulfonamide; iV-Benzyl-N-[4-(4-hydroxy-4-phenyl-piperidine- 1 -carbonyl)-phenyl]- benzenesulfonamide; iV-Benzyl-N-[4-(4-benzyl-4-hydroxy-piperidine-l-carbonyl)-ph enyl]- benzenesulfonamide; iV-(2,3-Dimethoxy-benzyl)-N-[4-(4-phenyl-piperazine-l-carbon yl)-phenyl]- benzenesulfonamide; iV-(4-Chloro-benzyl)-N-[4-(3-p-tolyl-piperidine-l-carbonyl)- phenyl]- benzenesulfonamide; iV-(4-Chloro-benzyl)-N- {4-[3 -(4-methoxy-phenyl)-piperidine- 1 -carbonyl]-phenyl} - benzenesulfonamide; 1 -Methyl- lH-imidazole-4-sulfonic acid benzyl-[2-methyl-4-(4-phenyl-piperazine-l- carbonyl)-phenyl]-amide;

1 -Methyl- lH-imidazole-4-sulfonic acid benzyl-[2-fluoro-4-(4-phenyl-piperazine-l- carbonyl)-phenyl]-amide; l-Methyl-lH-imidazole-4-sulfonic acid (4-methyl-benzyl)-[4-(4-phenyl-piperazine-l- carbonyl)-phenyl] -amide; 1 -Methyl- 1 H-imidazole-4-sulfonic acid (3-fluoro-benzyl)-[4-(4-phenyl-piperazine- 1 - carbonyl)-phenyl]-amide;

1 -Methyl- 1 H-imidazole-4-sulfonic acid (3 -methoxy-benzyl)- [4-(4-phenyl-piperazine- 1 - carbonyl)-phenyl]-amide; 1 -Methyl- 1 H-imidazole-4-sulfonic acid (4-chloro-benzyl)-{4-[3-(3-methyl-

[ 1 ,2,4]oxadiazol-5-yl)-piperidine- 1 -carbonylj-phenyl} -amide; l-Methyl-lH-imidazole-4-sulfonic acid (4-chloro-benzyl)-[4-(3-phenyl-piperidine-l- carbonyl)-phenyl]-amide; l-Methyl-lH-imidazole-4-sulfonic acid (4-chloro-benzyl)-[4-(3-phenoxy-piperidine-l- carbonyl)-phenyl]-amide;

1 -Methyl- 1 H-imidazole-4-sulfonic acid benzyl-[4-(2-phenyl-morpholine-4-carbonyl)- phenyl] -amide;

1 -Methyl- 1 H-imidazole-4-sulfonic acid benzyl- [4-(3 -phenyl-piperidine- 1 -carbonyl)- phenyl] -amide; 1 -Methyl- 1 H-imidazole-4-sulfonic acid benzyl-{4-[3-(3-methyl-[l,2,4]oxadiazol-5-yl)- piperidine- 1 -carbonyl] -phenyl} -amide; l,3-Dimethyl-lH-pyrazole-4-sulfonic acid benzyl-[4-(4-phenyl-piperazine-l-carbonyl)- phenyl] -amide;

2,3-Dimethyl-3 H-imidazole-4-sulfonic acid benzyl-[4-(4-phenyl-piperazine- 1 -carbonyl)- phenyl] -amide;

2 ,4-Dimethyl-thiazole-5 -sulfonic acid benzyl- [4-(4-phenyl-piperazine- 1 -carbonyl)- phenyl] -amide;

1 -Methyl- 1 H-imidazole-4-sulfonic acid benzyl-[4-(4-phenyl-piperazine- 1 -ylmethyl)- phenyl]-amide; 1 -Methyl- 1 H-imidazole-4-sulfonic acid benzyl-[2-fiuoro-4-(2-phenyl~morpholine-4- carbonyl)-phenyl]-amide; ^'

N-Benzyl-N-[4-(2-phenyl-morpholine-4-carbonyl)-phenyl]-di methylsulfamide;

N-Benzyl-N-[4-(2-phenyl-morpholine-4-carbonyl)-3-fluoroph enyl]-dimethylsulfamide;

N-(4-Fluoro)benzyl-N-[4-(2-phenyl-morpholine-4-carbonyl)- phenyl]-dimethylsulfamide; 4-{4-[Benzyl-(l-methyl-lH-imidazole-4-sulfonyl)-amino]-benzo yl}-2-phenyl- piperazine-1-carboxylic acid tert-butyl ester; 1 -Methyl- lH-imidazole-4-sulfonic acid benzyl-{4-[3-(4-fluoro-phenyl)-pyrrolidine~l- cafbonyl]-phenyl} -amide;

1-Methyl- lH-imidazole-4-sulfonic acid (4-chloro-benzyl)-[4-(piperidine-l -carbonyl)- phenyl] -amide; N-Benzyl-N-{4-[4-(2-cyano-phenyl)-piperazine-l-carbonyl]-phe nyl}-dimethylsulfamide;

N-Benzyl-N-{4-[3-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-pipe ridine-l-carbonyl]-phenyl}- diemthylsulfamide;

N-Benzyl-N-[4-(3-benzyIoxy-pyrrolidine-l-carbonyl)-phenyl ]-diemthylsulfamide;

N-Benzyl-N-[4-(4-hydroxy-4-phenyl-piperidine-l-carbonyl)- phenyl]-diemthylsulfamide; iV-Benzyl-N-[4-(4-phenoxy-piperidine- 1 -carbonyl)-phenyl]-diemthylsulfamide;

1 -Methyl- lH-imidazole-4-sulfonic acid benzyl-[4-(4-methyl-piperazine-l-carbonyl)- phenyl]-amide;

1 -Methyl- 1 H-imidazole-4-sulfonic acid benzyl-[4-(3 -methyl-piperidine- 1 -carbonyl)- phenyl]-amide; 1 -Methyl- 1 H-imidazole-4-sulfonic acid benzyl-{4-[4-(2-fluoro-phenyl)-piperazme-l- carbonyl]-phenyl} -amide;

1-Methyl- lH-imidazole-4-sulfonic acid benzyl-[4~(4-cyclohexylmethyl-piperazme-l- carbonyl)-phenyl]-amide;

1 -Methyl- 1 H-imidazole-4-sulfonic acid benzyl-[4-(4-methyl-3-phenyl-piperazine-l- carbonyl)-phenyl]-amide;

1 -Methyl- 1 H-imidazole-4-sulfonic acid benzyl-[4-(4-thiazol-2-yl-piperazine- 1 -carbonyl)- phenyl]-amide;

1 -Methyl- 1 H-imidazole-4-sulfonic acid benzyl-[4-(3-trifluoromethyl-piperidine-l- carbonyl)-phenyl]-amide; 1 -Methyl- 1 H-imidazole-4-sulfonic acid benzyl-[4-(4,4-difluoro-piperidine-l-carbonyl)- phenylj-amide;

1 -Methyl- 1 H-imidazole-4-sulfonic acid benzyl-[4-(3-fluoro-piperidine-l-carbonyl)- phenyl] -amide;

1 -Methyl- lH-pyrazole-3 -sulfonic acid benzyl-[4-(2-phenyI-morpholine-4-carbonyl)- phenylj-amide; 2-Methyl-2H-pyrazole-3-sulfonic acid benzyl-[4-(2-phenyl-morpholine-4-carbonyl)- phenyl]-amide; l-Methyl-lH-pyrazole-3-sulfonic acid (4-chloro-benzyl)-[4-(piperidine-l-carbonyl)- phenyl] -amide; Pyridine-3 -sulfonic acid (4-chloro-benzyl)-[4-(piperidine-l-carbonyl)-phenyl]-amide;

1 -Methyl- 1 H-pyrazole-3 -sulfonic acid benzyl-[4-(3 -phenyl-piperazine- 1 -carbonyl)- phenyl]-amide;

2-Methyl-2H-pyrazole-3-sulfonic acid benzyl-[4-(3-phenyl-piperazine-l-carbonyl)- phenyl] -amide; 1 -Methyl- lH-pyrazole-3-sulfonic acid benzyl-[4-(4-methyl-3-phenyl-piperazine-l- carbonyl)-phenyl]-amide;

2-Methyl-2H-pyrazole-3 -sulfonic acid benzyl- [4-(4-methyl-3 -phenyl-piperazine- 1 - carbonyl)-phenyl]-amide;

1 -Methyl- lH-imidazole-4-sulfonic acid (4-chloro-benzyl)-[4-(3-methyl-piperidine- 1- carbonyl)-phenyl]-amide;

1 -Methyl- lH-imidazole-4-sulfonic acid (3-chloro-benzyl)-[4-(piperidine-l-carbonyl)- phenyl] -amide;

1 -Methyl- 1 H-imidazole-4-sulfonic acid (4-fluoro-benzyl)-[4-(3 -methyl-piperidine- 1 - carbonyl)-phenyl]-amide; 1 -Methyl- 1 H-imidazole-4-sulfonic acid (4-methyl-benzyl)-[4-(3-methyl-piperidine-l- carbonyl)-phenyl]-amide;

1 -Methyl- 1 H-imidazole-4-sulfonic acid (3 ,4-dichloro-benzyl)-[4-(piperidine- 1 -carbonyl)- phenyl] -amide;

1 -Methyl- lH-imidazole-4-sulfonic acid (3-chloro-4-fluoro-benzyl)-[4-(piperidine- 1 - carbonyl)-phenyl]-amide;

1 -Methyl- 1 H-imidazole-4-sulfonic acid (4-chloro-benzyl)- [4-(2-methyl-pyrrolidine- 1 - carbonyl)-phenyl]-amide;

1 -Methyl- 1 H-imidazole-4-sulfonic acid (4-chloro-benzyl)-[4-(3 -methyl-pyrrolidine- 1- carbonyl)-phenyl]-amide; l-Methyl-lH-imidazole-4-sulfonic acid (4-chloro-benzyl)-[4-(3,3-difluoro-pyrrolidine-l- carbonyl)-phenyl]-amide; and pharmaceutically acceptable salts thereof.

As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic or ^-toluenesulfonic.

Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, arylalkyl amines or heterocyclic amines.

The compounds of the invention may contain one or more chiral centres. For the avoidance of doubt, the chemical structures depicted herein are intended to embrace all stereo isomers of the compounds shown, including racemic and non racemic mixtures and pure enantiomers and/or diastereoisomers.

As discussed herein, the compounds of the invention are useful in the treatment of various conditions. Thus, in a second aspect, the present invention provides a compound of formula (I) as defined herein for use in medicine. Preferably the compound is used to prevent or treat conditions which require inhibition of potassium channels, such as immunological disorders, including psoriasis, rheumatoid arthritis and multiple sclerosis.

In a further aspect the present invention provides a pharmaceutical formulation comprising at least one compound of formula I or as defined herein and optionally one or more excipients, carriers or diluents.

The compositions of the invention may be presented in unit dose forms containing a predetermined amount of each active ingredient per dose. Such a unit may be adapted to provide 5-100mg/day of the compound, preferably either 5-15mg/day, 10-30mg/day, 25- 50mg/day 40-80mg/day or 60-100mg/day. For compounds of formula I, doses in the range 100-lOOOmg/day are provided, preferably either 100-400mg/day, 300-600mg/day or 500-1000mg/day. Such doses can be provided in a single dose or as a number of discrete doses. The ultimate dose will depend on the condition being treated, the route of administration and the age, weight and condition of the patient and will be at the doctor's discretion.

The compositions of the invention may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).

Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For applications to the eye or other external tissues, for example the mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water- miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.

Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.

Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations may also include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.

The compositions of the invention can be used to treat conditions which require inhibition of potassium channels, for example in the treatment of immunological disorders. Thus, in further aspects, the present invention provides:

(i) A method of treating or preventing a disorder which requires potassium channel inhibition, eg immunological disorders comprising administering to a subject an effective amount of at least one compound of the invention or a pharmaceutical composition of the invention and

(ii) the use of a compound of the invention in the manufacture of a medicament for use in potassium channel inhibition.

In particular, the medicament is for use in the treatment or prevention of psoriasis, rheumatoid arthritis, multiple sclerosis and other immunological disorders. Preferred embodiments of the first aspect apply to all other aspects mutatis mutandis.

The compounds of formula (I) may be prepared by conventional routes, for example those set out in Schemes 1 to 5 shown below.

Scheme 1

Compounds of formula (I) in which X ₁ is C=O, X ₃ , X ₄ , R ₁ R ₃ , R ₁₀ and nare defined as above, may be prepared as shown in Scheme 1, from compounds of formula (VIII) where X ₁ is C=O, A is OH and Rj, R ₃ and R ₁₀ are defined as above and amines of formula (IX) where X ₃ , and X ₄ are defined as above. Typically, this reaction is carried out using a coupling reagent such as l-ethyl-3~(3-dimethylaminopropyl)-carbodiirnide (EDC) or 2- (7-aza-lH-benztriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU) utilising standard methods familiar to those skilled in the art such as reaction in solvent such as tetrahydrofuran, acetonitrile or dimethylformamide at a range of temperatures from ambient to reflux temperature. Alternatively, compounds of formula (I) in which X ₃ , X ₄ , R ₁ , R ₃ , R _1O and n are defined as above may be prepared from compounds of formula (VIII) where A is Cl or Br and amines of formula (IX). Typically, this reaction is performed in the presence of a base, for example, triethylamine, utilising standard methods familiar to those skilled in the art such as reaction in solvent such as tetrahydrofuran, acetonitrile or dichloromethane at a range of temperatures from ambient to reflux temperature. Compounds of formula (IX) are known compounds or may be prepared by standard published methods familiar to those skilled in the art. Scheme 2

Compounds of formula (VIII), where A is OH and R ₁ , R ₃ and Rio are defined as above may be prepared as show in Scheme 2, from compounds of formula (X) where AP is a suitably protected OH group such as a tert-butyl ester and R ₁ , R ₂ , R ₃ are defined as above, by standard methods familiar to those skilled in the art such as deprotection in the presence of a suitable acid, for example trifluoroacetic acid, utilizing a solvent such as tetrahydrofuran, acetonitrile or dichloromethane, at a range of temperatures from O ⁰ C to reflux temperature.

Compounds of formula (X) may be prepared from sulfonamides (XII) where R ₃ and Rio are defined as above, utilizing standard methods familiar to those skilled in the art such as, reaction with an electrophile with the formula R ₁ -Y where R ₁ is defined as above and Y is Cl or Br in the presence of a base, for example cesium carbonate and a solvent such as tetrahydrofuran, acetonitrile or dichloromethane at a range of temperatures from ambient to reflux temperature. Alternatively, compounds of formula (X) may be prepared from amines (XI) where R ₁ and R ₃ are defined as above by standard methods familiar to those skilled in the art such as, reaction with a sulfonyl or sulfamoyl chloride with the formula R ₁₀ -SO ₂ Cl in the presence of a base, for example pyridine, triethylamine or potassium carbonate and a solvent such as tetrahydrofuran, acetonitrile or dichloromethane, at a range of temperatures from ambient to reflux temperature.

Compounds of formula (XII) are known compounds or may be prepared from compounds of formula (XIII) where R ₃ is defined as above by standard methods familiar to those skilled in the art, such as reaction with a sulfonyl or sulfamoyl chlorides with the formula R _1O -SO ₂ Cl in the presence of a base, for example potassium carbonate, triethylamine or pyridine, and a solvent such as dichloromethane, tetrahydrofuran and acetonitrile, at a range of temperatures from ambient to reflux temperature.

Compounds of formula (XI) are known compounds or may be prepared from compounds of formula (XIII) by standard methods familiar to those skilled in the art such as, alkylation with an electrophile with the formula R ¹ -Y where R ¹ is defined as above and Y is Cl or Br in the presence of a base, for example potassium carbonate, triethylamine or pyridine and a solvent such as dichloromethane, tetrahydrofuran and acetonitrile at a range of temperatures from ambient to reflux temperature. Alternatively, Compounds of formula (XI) may be prepared from compounds of formula (XIII) by standard methods familiar to those skilled in the art, such as reductive amination with an aldehyde with the formula R ¹ -Y where R ¹ is defined as above and Y is CHO in the presence of a reducing agent, for example sodium triacetoxyborohydride, and a solvent such as dichloromethane, tetrahydrofuran and acetonitrile at a range of temperatures from ambient to reflux temperature. Compounds of formula (XIII) are known compounds or may be prepared by standard methods familiar to those skilled in the art.

Scheme 3

R _Γ Y R _Γ Y Compounds of formula (I) in which R ₂ is SO ₂ Ri ₀ and X ₁ , X ₃ , R ₁ , R ₃ , R ₁₀ and n are defined as above may be prepared as shown in Scheme 3, from amines of formula (XVI) and sulfonyl or sulfamoyl chlorides with the formula R ₁₀ -SO ₂ Cl in the presence of a base, for example triethylamine, diisopropylamine or pyridine, utilizing standard methods familiar to those skilled in the art such as reaction in solvent, for example tetrahydrofuran, acetonitrile, dichloromethane or toluene, at a range of temperatures from ambient to reflux temperature. Alternatively, compounds of formula (I) may be prepared from compounds of formula (XIV) by standard methods familiar to those skilled in the art such as reaction with an electrophile with the formula R ₁ -Y where R] is defined as above and Y is Cl or Br in the presence of a base, for example cesium carbonate and a solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene, at a range of temperatures from ambient to reflux temperature.

Compounds of formula (I) in which Xi is CH ₂ , R ₂ is SO ₂ Ri _O , and X ₃ , X ₄ , Ri, R ₃ , Ri ₀ and n are defined as above may be prepared from compounds of formula (I) wherein Xi is C=O by standard methods familiar to those skilled in the art such as, reduction in the presence of a reducing agent, for example lithium aluminium hydride and a suitable solvent such as tetrahydrofuran or diethylether at a range of temperatures from ambient to reflux temperature.

Compounds of formula (XVI) wherein Xi, X ₃ , X ₄ , Ri, R ₃ and n are defined as above are either known compounds or may be prepared from amines of formula (XV) by standard methods to those skilled in the art such as, alkylation with an electrophile with the formula Ri-Y where Ri is defined as above and Y is Cl or Br in the presence of a base, for example potassium carbonate, triethylamine or pyridine and a solvent such as tetrahydrofuran, dichloromethane or acetonitrile at a range of temperatures from ambient to reflux. Alternatively, compounds of formula (XVI) may be prepared from compounds of formula (XV) by reductive amination with an electrophile with the formula Ri-Y where Ri is defined as above and Y is CHO in the presence of a reducing agent such as sodium triacetoxyborohydride utilizing standard methods familiar to those skilled in the art such as reaction in a solvent, for example tetrahydrofuran, dichloromethane or acetonitrile at a range of temperatures from ambient to reflux.

Compounds of formula (XIV) wherein X ₁ , X ₃ , X ₄ , R ₃ , R _1O and n are defined as above are known compounds or may be prepared from amines of formula (XV) and sulfonyl or sulfamoyl chlorides with the formula Ri _O -SO ₂ Cl in the presence of a base, for example triethylamine, diisopropylamine or pyridine, utilizing standard methods familiar to those skilled in the art such as reaction in solvent, for example, tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature.

Scheme 4

(XIX) (XV)

(XVIII)

Compounds of formula (XV) in which Xi is C=O, X ₃ , X ₄ , R ₃ , and n are defined as above, are known compounds or may be prepared as shown in Scheme 4, from compounds of formula (XIX) wherein Xi is C=O, A is OH and R ₃ is defined as above, and compounds of formula (IX) together with a coupling reagent such as l-ethyl-3-(3- dimethylaminopropyl)-carbodiimide (EDC) or 2-(7-aza-lH-benztriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate (HATU) utilising standard methods familiar to those skilled in the art such as reaction in solvent, for example tetrahydrofuran, acetonitiile or dimethylformamide at range of temperatures from ambient to reflux temperature.

Compounds of formula (XV) in which X ₁ is CH ₂ , X ₃ , X ₄ , R ₃ , and n are defined as above are known compounds or may be prepared from compounds of formula (XIX) wherein

X ₁ is CH ₂ and A is a leaving group such as Cl or Br and compounds of formula (IX) by standard methods familiar to those skilled in the art such as alkylation in the presence of a base, for example triethylamine, diisopropylamine or pyridine and a solvent such as tetrahydrofuran, acetonitiile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature.

Compounds of formula (XV) in which X ₁ is CH ₂ , X ₃ , X ₄ , R ₁ , R ₃ , and n are defined as above, may be prepared from compounds of formula (XIX) wherein Xi is C=O and A is H and compounds of formula (IX) by standard methods familiar to those skilled in the art such as reductive amination in the presence of a reducing agent, for example sodium triacetoxyborohydride and a solvent such as tetrahydrofuran, acetonitiile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature. Alternatively, compounds of formula (XV) in which Xi is CH ₂ , X ₄ is CH ₂ , X ₃ , R ₁ , R ₃ , and n are defined as above, may be prepared from compounds of formula (XV) wherein X ₁ is C=O by standard methods familiar to those skilled in the art such as reduction in the presence of a reducing agent, for example lithium aluminium hydride and a solvent such as tetrahydrofuran or diethylether at a range of temperatures from ambient to reflux.

Compounds of formula (XV) in which X ₁ is a chemical bond, CH ₂ or C(=O) and X ₃ , X ₄ , R ₃ , and n are defined are known compounds or may be prepared as shown in scheme 4, from compounds of formula (XVII) where X ₁ is a chemical bond, CH ₂ or C(=O) by standard methods familiar to those skilled in the art such as reduction using a reducing agent, for example tin(II)chloride and a suitable solvent such as ethyl alcohol at a range of temperatures from ambient to reflux. Compounds of formula (XVII) in which Xi is CH ₂ or C(=O) may be synthesised from nitro compounds (XVIII) in which A is a leaving group such as Cl or Br and compounds of formula (IX) by standard methods familiar to those skilled in the art using a base such as pyridine, triethylamine or potassium carbonate and a suitable solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature.

Scheme 5

(XXII) (XXI)

Compounds of formula (XVII) in which X ₁ is a chemical bond X ₃ , X ₄ , R ₃ , and n are defined as above are known compounds or may be prepared, from compounds of formula (XX) and compounds of formula (IX) utilizing a base such as N-methyl morpholine by standard methods familiar to those skilled in the art, for example reaction in a solvent such as dichloromethane, acetonitrile, tetrahydrofuran or NN-dimethylformamide at a range of temperatures from ambient to reflux. Alternatively, compounds of formula (XVII) in which X ₁ is a chemical bond, may be prepared from compounds of formula (XXII) by standard methods familiar to those skilled in the art such as reaction with electrophiles of formula (XXI) wherein Y is Cl or Br in the presence of a base, for example pyridine or triethylamine and a suitable solvent such as dichloromethane, acetonitrile or tetrahydrofuran at a range of temperatures from ambient to reflux. Compounds of formula (XX), (XXII) and (XXI) are known compounds or may be prepared by known methods familiar to those skilled in the art.

The compounds of the invention are found to be inhibitors of potassium channels (K _v ) and are therefore therapeutically useful. Such compounds are believed to be novel and the present invention also provides for these compounds. The examples which follow are illustrative and, as recognized by one skilled in the art, particular reagents or conditions could be modified as needed for individual compounds. Many of the starting materials referred to in the reactions described above are available from commercial sources or can be made by methods cited in the literature references.

Examples

HPLC analysis was conducted using the following methods:

Solvent : [MeCN-0.05% HCO ₂ H : H ₂ O-0.1% HCO ₂ H], 10-95% gradient 3min, 95% 2.5min; Column: Phenomenex Gemini 50x4.6 mm i.d., Cl 8 reverse phase; Flow rate: 0.75mL/min unless otherwise indicated.

Solvent : [MeCN-0.05% HCO ₂ H : H ₂ O-0.01% HCO ₂ H], 5-95% gradient 5min, 95% 3min; Column: Phenomenex Gemini 50x4.6 mm i.d. , Cl 8 reverse phase; Flow rate: 1.5mL/min unless otherwise indicated.

Solvent : [MeCN : H ₂ O-0.1% HCO ₂ H], 5-95% gradient 3.5min, 95% 2min; Column: Phenomenex Gemini 50x3 mm i.d. , C18 reverse phase; Flow rate: lmL/min unless otherwise indicated.

Solvent : [MeCN-0.05% HCO ₂ H : H ₂ O-0.1% HCO ₂ H], 5-95% gradient 6min, 95% 3min; Column: Phenomenex Gemini 50 x 4.6 mm i.d. , Cl 8 reverse phase; Flow rate: lmL/min unless otherwise indicated. Preparative HPLC purification was conducted in the following manner: Solvent : [MeCN-0.05% HCO ₂ H : H ₂ O-0.1% HCO ₂ H], 5-95% gradient 12min, 95% 3min; Waters X-Bridge 100x19 mm i.d. , Cl 8 reverse phase; Flow rate: 16mL/min unless otherwise indicated.

Example 1) N~(4-Chloro-benzyl)-JV-[4-(4-phenyl-piperazine-l-carbonyl)-p henyl]- benzenesulfonamide (Method A)

i) (4-Nitro-phenyl)-(4-phenyl-piperazin-l-yl)-methanone To a stirred solution of 4-nitrobenzoyl chloride (6.23g, 33.9mmol) and N-phenyl piperazine (4.71ml, 30.8mmol) in anhydrous dioxane (250ml) at O ⁰ C was added triethylamine (4.73ml, 33.9mmol) and the mixture was then stirred at reflux (HO ⁰ C) for 5 hours. The reaction was allowed to cool then quenched with water (100ml) and the resulting aqueous mixture was extracted with ethyl acetate (2 x 75ml). The organic extracts were combined, dried over magnesium sulfate and concentrated to yield crude product as a yellow oil. Pure product was obtained by crystallisation from a mixture of 40% ethyl acetate in petrol to afford the title compound as a white crystalline solid (6.5g, 62%). HPLC retention time 6.9min. Mass spectrum (ES+) m/z 312 (M+H).

The following compound was synthesised according to the method described using the appropriate starting materials:

l-(4-Nitro-benzenesulfonyl)-4-phenyl-piperazine

H) (4-Amino-phenyl)-(4-phenyl-piperazin-l-yl)-methanone

A solution of tin chloride dihydrate (5.44g, 24.1mmol) in concentrated hydrochloric acid (32ml) was added slowly to a cooled, stirred solution of (4-nitro-phenyl)-(4-phenyl- piperazin-l-yl)-methanone (l.Og, 3.2mmol) in anhydrous diethyl ether (32ml). The resulting mixture was stirred for 1 hour at room temperature, then cooled and quenched carefully with 1OM sodium hydroxide (aq.) until slightly basic (~pH 9). The aqueous mixture was extracted with ethyl acetate (100ml) and the organic extracts dried over magnesium sulfate then concentrated in vacuo to the title compound as a cream solid (667mg, 73% yield). HPLC retention time 6.2min. Mass spectrum (ES+) m/z 282 (M+H).

Ui) [4-(4-Chloro-benzylamino)-phenyl]-(4-phenyl-piperazin-l-yl)- methanone

To a stirred solution of (4-amino-phenyl)-(4-phenyl-piperazin-l-yl)-methanone (200mg, 0.71mmol) in 1,2-dichloroethane (4ml) at O ⁰ C was added 3-chlorobenzaldehyde (99.7mg, 0.71mmol). Sodium triacetoxy borohydride (210mg, 0.99mmol) and acetic acid (40.6μl, 0.71mmol) were added and the reaction was stirred at room temperature under nitrogen overnight. The reaction was quenched with the addition of sodium hydroxide (aq.) (pH8) and extracted with diethyl ether (3 x 20ml). The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound as a yellow solid (72mg, 25% yield). HPLC retention time 7.5min. Mass spectrum (ES+) m/z 406 (M+H).

The following compounds were synthesised according to the method described using the appropriate starting materials:

(4-Benzylamino-phenyl)-(4-phenyl-piperazin-l-yl)-methanon e [4-(3-Chloro-benzylamino)-phenyl]-(4-phenyl-piperazin-l~yl)- methanone [4-(2-Chloro-benzylamino)-phenyl]-(4-phenyl-piperazin-l-yl)- methanone [4-(4-Fluoro-benzylamino)-phenyl]-(4-phenyl~piperazin-l-yl)- methanone [4-(3,4-Dimethoxy-benzylamino)-phenyl]-(4-phenyl-piperazin-l -yl)-methanone Benzyl-[4-(4-phenyl~piperazine-l-sulfonyl)-phenyl] -amine (4-Fluoro-benzyl)-[4-(4-phenyl-piperazine-l-sulfonyl)-phenyl ] -amine

iv) N-(4-Chloro-benzyl)-N-[4-(4-phenyl-piperazine-l-carbonyl)-ph enyl]- benzenesulfonamide (1)

To a stirred solution of [4-(4-chloro-benzylammo)-phenyl]-(4-phenyl-piperazin-l-yl)- methanone (30mg, 0.07mmol) and phenylsulfonyl chloride (14.2μl, O.llmmol) in anhydrous dichloromethane (ImI) was added pyridine (7.2μl, 0.09mmol) and the reaction was stirred at ambient for 18 hours. PS-trisamine (32mg, 0.13mmol) was added and the mixture was agitated for 3 hours then filtered. The filtrate was concentrated in vacuo to afford the title compound as a yellow solid (48mg, 98% yield). HPLC retention time 7.7min. Mass spectrum (ES+) m/z 547 (M+H).

Other compounds prepared by Method A as described for example 1 using the appropriate starting materials are listed in TABLE 1

Example 2) N-(4-Cyano-benzyI)-iV-[4-(4-phenyl-piperazine-l-carbonyl)-ph enyl]- benzenesulfonamide (Method B)

i) (4-Amino-phenyl)-(4-phenyl-piperazin-l-yl)-methanone

To a stirred suspension of 4-aminobenzoic acid (5g, 36.5mmol) in acetonitrile (100ml) was added l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (7.67g, 40.2mmol), hydroxybenzotriazole hydrate (0.49g, 3.65mmol), 1-phenylpiperazine (11.2ml, 3.65mmol) followed by triethylamine (12.8ml, 91.3mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction was diluted with the addition of water and the resulting aqueous mixture extracted using dichloromethane (3 x 100ml). The organics were combined, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash column chromatography (SiO ₂ ) eluting with ethylacetate/dichloromethane (1:1) to afford the title compound as an off white solid. HPLC retention time 7.1min. Mass spectrum (ES+) m/z 282 (M+H).

The following compounds were synthesised according to the method described using the appropriate starting materials:

(4-Amino-3-fluoro-phenyl)-(4-phenyl-piperazin-l-yl)-metha none (4-Amino-3-methyl-phenyl)-(4-phenyl~piperazin-l-yl)-methanon e

U) 4-{[4-(4-Phenyl-piperazine-l-carbonyl)-phenylamino]-methyl}- benzonitrile To a stirred solution of (4-amino-phenyl)-(4-phenyl-piperazin-l-yl)-methanone (0.5g, 1.78mmol) in tetrahydrofuran (1OmL) was added 4-cyanobenzaldehyde (0.4g, 2.67mmol) followed by sodium borohydride and the reaction was heated to 5O ⁰ C for 2 hours. On cooling, the reaction was quenched by the addition of water (1OmL) and the aqueous solution basifϊed by the addition of ammonium chloride (~pH 8). The aqueous mixture was extracted using dichloromethane (3 x 10ml) and the organic extracts combined, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as an off white solid (604mg, 98% yield). HPLC retention time 7.17min. Mass spectrum (ES+) m/z 397 (M+H).

The following compounds were synthesised according to the method described using the appropriate starting materials:

[4-(4-Dimethylaτnino-benzylamino)-phenyl]-(4-phenyl-pipe razin-l-yl)-methanone [4-(4-tert-Butoxy-benzylamino)-phenyl]-(4-phenyl-piperazin-l -yl)-methanone [4-(3-Fluoro-benzylamino)-phenyl]-(4-phenyl-piperazin-l-yl)- methanone [4-(2-Methoxy-benzylamino)-phenyl]-(4-phenyl-piperazin-l-yl) -methanone [4-(3-Methoxy-benzylamino)-phenyl]-(4-phenyl-piperazin-l-yl) -methanone [4-(4-Methoxy-benzyla?nino)-phenyl]-(4-phenyl-piperazin-l-yl )-methanone {4-[(Biphenyl-4-ylmethyl)-amino]-phenyl}-(4-phenyl-piperazin -l-yl)-methanone (4-Phenyl-piperazin-l-yl)-{4-[(pyridin-3-ylmethyl)-amino]-ph enyl}-methanone [4~(2-Methyl-benzylamino)-phenyl]-(4-phenyl-piperazin-l-yl)- methanone [4-(4-Methyl-benzylamino)-phenyl]-(4-phenyl-piperazin-l-yl)- methanone {4-[(Naphthalen-2-ylmethyl)-aminoJ-phenyl}-(4-phenyl-piperaz in-l-yl)-methanone {4-[(Naphthalen-l-ylmethyl)-amino]-phenyl}-(4-phenyl-piperaz in-l-yl)-methanone [4-(Cyclopentylmethyl-amino)-phenyl]-(4-phenyl-piperazin-l-y l)-methanone 4-{[4-(4-Phenyl-piperazine-l-carbonyl)-phenylaminoJ '-methyl} -benzoic acid methyl ester (4-Phenyl-piperazin-l-yl)-[4-(4-trifluoromethyl-benzylarnino )-phenyl]-methanone (4-Phenyl-piperazin-l-yl)-[4-(2-trifluoromethoxy-benzylamino )-phenyl]-methanone (4-Phenyl-piperazin-l-yl)-[4-(3-trifluoromethoxy-benzylamino )-phenyl]-methanone (4-Phenyl-piperazin-l-yl)-[4-(4-trifluoromethoxy-benzylamino )-phenyl]-methanone 2-{[4-(4-Phenyl-piperazine-l-carbonyl)-phenylamino]-tnethyl} -benzonitrile (4-Phenyl-piperazin-l-yl)-{4-[(thiophen-3-ylmethyl)-aminoJ-p henyl}-methanone {4-[(Furan-3-ylmethyl)-amino]-phenyl}-(4-phenyl-piperazin-l- yl)-methanone {4-[(Furan-2-ylmethyl)-amino]-phenyl}-(4-phenyl-piperazin-l- yl)-methanone (4-Phenethylamino-phenyl)-(4-phenyl-piperazin-l-yl)-methanon e

[4-(Cyclopropylmethyl-arnino)-phenyl]-(4-phenyl-piperazin -l-yl)-methanone [4-(2-Benzyloxy-ethylamino)-phenyl]-(4-phenyl-piperazin-l-yl )-methanone [4-(Cyclohexylmethyl-amino)-phenyl]-(4-pheiιyl-piperazin-l- yl)-methanone (4-Phenyl-piperazin-l-yl)-[4-(3-phenyl-propylamino)-phenyl]- methanone {4-[(l-Methyl-lH-pyrazol-4-ylmethyl)-amino]-phenyl}-(4-pheny l-piperazin-l-yl)- methanone

(4-Benzylamino-3-fluoro-phenyl)-(4-phenyl-piperazin-l-yl) -methanone (4-Benzylamino-3-methyl-phenyl)-(4-phenyl-piperazin-l-yl)-me thanone [4-(2-Ethoxy-benzylamino)-phenyl]-(4-phenyl-piperazin-l-yl)- methanone [4-(2, 3-Dimethoxy-benzylamino)-phenyl]-(4-phenyl-piperazin-l-yl)-r nethanone [4-(3-Methoxy-benzylamino)-phenyl]-(4-phenyl-piperazin-l-yl) -methanone

Ui) N-(4-Cyano-benzyl)-N-[4-(4-phenyl-piperazine-l-carbonyl)-phe nyl]- benzenesulfonamide (2)

A mixture of 4-{[4-(4-Phenyl-piperazine-l-carbonyl)-phenylamino]-methyl}- benzonitrile (50mg, 0.13mmol), phenylsulfonylchloride (80mg, 0.42mmol) and pyridine (0.04mL, 0.44mmol) in dichloromethane (5 ml) was heated to reflux for lόhours. The reaction mixture was cooled to room temperature and the quenched by the addition of water (4 ml). The organics were collected, dried over magnesium sulfate and concentrated in vacuo The residue was purified by preparative thin layer chromatography (dichloromethane/ethyl acetate 1:1) to afford the title compound as a white solid (16.4mg, 27% yield). HPLC retention time 6.71min. Mass spectrum (ES+) m/z 475 (M+H).

Other compounds prepared by Method B as described for example 2 using the appropriate starting materials are listed in TABLE 1 Example 3) iV-Benzyl-iV-[4-(piperidine-l-carbonyI)-phenyI]-benzenesulfo namide: (Method C)

i) 4-Benzylamino-benzoic acid

To a stirred solution of 4-aminobenzoic acid (1Og, 73mmol) in tetrahydrofuran (200ml) was added benzaldehyde (9.63ml, 95mmol), acetic acid (4.9ml, 91.3mmol) followed by sodium triacetoxyborohydride (3 Ig, 146mmol) and the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (200ml) and extracted with dichloromethane (2 x 200ml). The organics were combined, washed with brine, dried over magnesium sulfate and then concentrated in vacuo. The residue was purified by flash chromatography (SiO ₂ ) eluting with diethylether/dichloromethane (1:4) to afford the title compound as an off white solid (4.74g ₅ 28% yield). HPLC retention time 5.32min. Mass spectrum (ES+) m/z 228 (M+H).

U) (4-Benzylamino-phenyl)-piperidin-l-yl-methanone

To a stirred suspension of 4-(benzylammo)benzoic acid (200mg, 0.88mmol) in acetonitrile (2ml) was added piperidine (0.174ml, l.δmmol), l-ethyl-3-(3- dimethylaminopropyl)-carbodiimide hydrochloride (184mg, 0.97mmol), hydroxybenzotriazole hydrate (lOmg, catalytic) followed by triethylamine (0.31ml, 2.2mmol) and the reaction was stirred at room temperature for 16hours. The reaction mixture was diluted with water (2ml) and extracted with dichloromethane (2 x 2ml). The organic phases were combined, washed with brine, dried over magnesium sulfate and then concentrated in vacuo. The residue was purified by flash column chromatography (SiO ₂ ) eluting with ethyl acetate/dichloromethane (1:4) to afford the title compound as an off white solid (122mg, 47% yield).

The following compounds were synthesised according to the method described using the appropriate starting materials: (4-Benzylamino-2-methyl-phenyl)-(4-phenyl-piperazin-l-yl)-me thanone (4-Benzylamino-3-βιιoro-phenyl)-(4-phenyl~piperazin-l-yl) -methanone (4-Benzylamino-2~inethoxy-phenyl)-(4-phenyl-piperazin-l-yl)- methanone N-Benzyl-N-{4-[4-(2-methoxy-ethyl)-piperazine-l-carbonyl] -phenyl}- benzenesulfonamide

N-Benzyl-N-{4-[4-(2-oxo-2-pyrrolidin-l-yl-ethyl)-piperazi ne-l-carbonyl]-phenyl}- benzenesulfonamide

(4-Benzylamino-phenyl)-(3,4-dihydro-lH-isoquinolin-2-yl)- methanone (4-Benzylamino-phenyl)-(2,6-dimethyl-morpholin-4-yl)-methano ne

Ui) N-Benzyl-N~[4-(piperidine-l-carbonyl)-phenyl]-benzenesulfona mide (5)

To a stirred solution of (4-benzylamino-phenyl)-piperidin-l-yl-methanone (39mg, 0.14mmol) in dichloromethane (ImI) was added benzene sulfonylchloride (57 μl, 0.46mmol) followed by pyridine (42μl, 0.5mmol) and the reaction was heated to 4O ⁰ C for 20 hours. The reaction was allowed to cool to room temperature and partitioned between water (5ml) and dichloromethane (5ml). The organics were collected, concentrated in vacuo and purified by preparative TLC to afford the title compound as a white solid (38mg, 62% yield). HPLC retention time 5.8min. Mass spectrum (ES+) m/z 435 (M+H).

Other compounds prepared by Method C as described for example 3 using the appropriate starting materials are listed in TABLE 1

Example 4) iV-(4-ChIoro-benzyI)-N-[4-(3-p-tolyl-piperidine-l-carbonyl)- phenyl]- benzenesulfonamide : (Method D)

i) 4-(4-Chloro-benzylamino)-benzoic acid tert-butyl ester

To a stirred solution of 4-chlorobenzaldehyde (5.46g, 39mmol) in dichloromethane (50ml) was added tert-butyl-4-amino benzoate (5.Og, 26mmol), acetic acid (2.23ml, 39mmol) followed by sodium triacetoxyborohydride (13.7g, 65mmol) and the reaction was stirred at room temperature for 16 hours. The reaction mixture was quenched by addition to ice (100ml) and the resulting aqueous solution neutralized using sodium carbonate (solid). The aqueous mixture was extracted using dichloromethane (3 x 100ml) and the organics were combined, dried over magnesium sulfate and then concentrated in vacuo to afford the title compound as a white solid (1Og, 81% yield). HPLC retention time 8.09min. Mass spectrum (ES+) m/z 318 (M+H).

The following compounds were synthesised according to the method described using the appropriate starting materials:

4-(B enzylamino) -benzoic acid tert-butyl ester

4-(4-Fluoro-benzylamino)-benzoic acid tert butyl ester

4-(Benzylamino)-3-fluoro-benzoic acid tert butyl ester

U) 4-[Benzenesulfonyl-(4-chloro-benzyl)-amino]-benzoic acid tert-butyl ester

A mixture of 4-(4-chloro-benzylamino)-benzoic acid tert-butyl ester (6g, 6.3mmol), phenylsulfonylchloride (2.9ml, 21mmol) and pyridine (1.86mL, 23mmol) in dichloromethane (25mL) was heated to reflux for lόhours. The reaction mixture was cooled to room temperature, diluted with dichloromethane (25ml) and washed with water

(2 x 25ml). The organics were collected, dried over magnesium sulfate and concentrated in vacuo to afford a yellow oil which was purified by flash chromatography

(hexanes/ethyl acetate 9:1) to afford the title compound as a white solid (2.2g, 76% yield). HPLC retention time 8.54min.

The following compounds were synthesised according to the method described using the appropriate starting materials:

4-[Benzyl-(l-methyl-lH-imidazole-4-sulfonyl)-amino]-betι zoic acid tert-butyl ester

4-[(4-Chloro-benzyl)-(l-methyl-lH-imidazole-4-sulfonyl)-a mino] -benzoic acid tert-butyl ester

4-[(4-Fluoro-benzyl)-(l-methyl-lH-imidazole-4-sulfonyl)-a mino] -benzoic acid tert butyl ester

4-[Benzyl-(l-methyl-lH-imidazole-4-sulfonyl)-amino]-3-flu oro-benzoic acid tert butyl ester 4-(Benzenesulfonyl-benzyl-amino)-benzoic acid tert-butyl ester Hi) 4-[Benzenesulfonyl-(4-chloro-benzyl)-amino]-benzoic acid

A solution of 4-[benzenesulfonyl-(4-chloro-benzyl)-amino]-benzoic acid tert-butyl ester

(2.1g, 4.4mtnol) in 10% trifluoroacetic acid/dichloromethane (5OmL) was stirred at room temperature for lόhours. The reaction mixture was concentrated in vacuo and the residue partitioned between sodium hydrogen carbonate (saturated solution, 25mL) and dichloromethane (2OmL). The aqueous layer was separated, acidified (pH 1) using 10%

HCl (aq) and the resulting solution extracted with dichloromethane (3 x 75mL). The organics were combined, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a white solid ( 1.1 g, 62% yield)

The following compounds were synthesised according to the method described using the appropriate starting materials:

4-[Benzyl-(l-methyl-lH-imidazole-4-sulfonyl)-amino] -benzoic acid 4-[(4-Chloro-benzyl)-(l-methyl-lH-imidazole-4-sulfonyl)-amin o] -benzoic acid 4-[(4-Fluoro-benzyl)-(l-methyl-lH-imidazole~4-sulfonyl)-amin o] -benzoic acid 4-[Benzyl-(l-methyl~lH-imidazole-4-sulfonyl)-amino]-3-fluoro -benzoic acid 4 -(B enzenesulfonyl-benzyl-amino) -benzoic acid

iv) N-(4-Chloro-benzyl)-N-[4-(3-p-tolyl-pipeήdine-l-carbonyl)-p henyl]- benzenesulfonamide (4)

To a stirred solution of 4-[benzenesulfonyl-(4-chloro-benzyl)-amino]-benzoic acid (50mg, 0.13mmol) in acetonitrile (ImL) was added 3-(4-methylphenyl)piperidine (40mg, 0.19mmol), l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) (24mg, 0.13mmol) followed by 1-hydroxybenzotriazole (HOBt) (1.7mg, 0.013mmol) and the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (3ml) and extracted with dichloromethane (3 x 2ml). The organic extracts were combined, dried over magnesium sulfate then concentrated in vacuo and the resulting residue purified by flash chromatography (dichloromethane/ethylacetate 9:1) to afford the title compounds as a white foam (31mg, 44% yield). HPLC retention time 8.25min. Mass spectrum (ES+) m/z 559 (M+H). Other compounds prepared by Method D as described for example 4 using the appropriate starting materials are listed in TABLE 1

Example 5) iV-Benzyl-N'N'-dimethyl-iV-{4-[4-(2-cyano-phenyl)-piperazine -l- carbonyl]-phenyl}-sulfamide : (Method E)

i) N-Benzyl-N'N'~dimethyl-N-(4-benzoic acid tert-butyl ester)-sulfamide

A solution of 4-benzylamino-benzoic acid tert-butyl ester (2g, 7mmol) and N,N~ dimethylsulfamoyl chloride (3.8ml, 35mmol) in pyridine (20ml) was heated to 100 ⁰ C for 2 hours. The reaction mixture was cooled to room temperature and ,JV-dimethylsulfamoyl chloride (ImI, 9mmol) was added and the reaction heated to 100 ⁰ C for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo using toluene (3 x 100ml) as an azeotrope. The residue was washed with ethyl acetate (3 x 100ml) and the washings concentrated in vacuo to afford an orange oil. The oil was purified by flash chromatography on silica gel eluting with 15% ethylacetate/hexanes to afford the title compound as a white solid. HPLC retention time 6.75min. ¹ HNMR (CDCl ₃ ) δ _H 1.56, s (9H), 2.77, s (6H), 4.85, s (2H), 7.18-7.27, m (5H), 7.33, d (2H, J= 8.84), 7.9, d (2H, J=8.84).

U) N-Benzyl-N'N'-dimethyl-N-(4-benzoic acid)sulfamide

A solution of iV-Benzyl-N-(4-benzoic acid tert-butyl ester)-NW'-dimethylsulfamide (Ig, 2.5mmol) in dichloromethane (80ml) was cooled to O ⁰ C. Trifluoroacetic acid (20ml) was added drop-wise over 5 minutes and the reaction warmed to room temperature then stirred for 2 hours. The reaction mixture was concentrated in vacuo and the residue triturated using hexanes (100ml). Filtration of the resulting suspension gave the title compound as a beige solid (0.7g, 84%). HPLC retention time 4.28min. Mass spectrum (ES+) 333 (M+H).

in) N-Benzyl-N'N'-dimethyl-N-fe-ft-tø-cyano-phenyty-piperazine- l-carbonylJ-phenyl}- sulf amide (5) To a stirred solution of l-(2-cyanophenyl)-piperazine (32mg, 0.17mmol) in dry dimethylformamide (ImI) was added JV-benzyWVW'-dimethyl-iV-(4-benzoie acid)sulfamide (50mg, 0.15mmol), triethylamine (0.065ml, 0.45mmol) and 2-(7-aza- lH-benzotriazole- 1 -yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate (63mg, 0.17mmol) and the reaction was stirred at room temperature for 16 hours. The solvent was removed under vacuum and the residue purified by preparative HPLC. HPLC retention time 6.0min. Mass spectrum (ES+) m/z 504 (M+H).

Other compounds prepared by Method E as described for example 5 using the appropriate starting materials are listed in TABLE 1

Example 6) iV-Benzyl-iV-[4-(2-phenyl-morpholine-4-carbonyl)-phenyl]-N', N'- dimethylsulfamide (Method F)

i) (4-Amino-phenyl)-(2-phenyl-morpholin-4-yl)-methanone

To a stirred suspension of benzoic acid (160mg, lmmol) and 2-phenylmorpholine hydrochloride (300mg, 1.5mmol) in acetonitrile (10ml) was added triethylamine (0.4ml, 3mmol) followed by HATU and the reaction mixture was stirred at room temperature for 16 hours. The reaction was diluted with dichloromethane (25ml) and washed with sodium hydrogen carbonate (25ml, saturated solution). The organics were collected, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethylacetate to afford the title compound as a clear oil (240mg, 84% yield). HPLC retention time 5.05min. Mass spectrum (ES+) m/z 283 (M+H).

H) (4-Benzylamino-phenyl)-(2~phenyl-morpholin-4-yl)-methanone Benzaldeyhde (0.1ml, lmmol) was added to a stirred solution of (4-amino-phenyl)-(2- phenyl-morpholin-4-yl)-methanone (240mg, 0.84mmol) in dichloromethane (20ml) and the resulting mixture was heated to 45 ⁰ C for 2 hours. The reaction mixture was cooled to room temperature then sodium triacetoxyborohydride (250mg, 1.2mmol) was added and the reaction was stirred at room temperature for 48 hours. The reaction was diluted with dichloromethane (10ml) and quenched by the addition of water (10ml). The aqueous was washed with dichloromethane (2 x 10ml), the organics combined and dried over magnesium sulfate. The solvent was concentrated in vacuo and the residue purified by flash chromatography to afford the title compound as a colourless oil (0.22g, 70% yield). HPLC retention time 6.18min. Mass spectrum (ES+) m/z 373 (M+H).

Hi) N-Benzyl-N-[4-(2-phenyl-morpholine-4-carbonyl)-phenyl]-N',N' - dimethylsulfamide (6)

A solution of (4-benzylamino-phenyl)-(2-phenyl-morpholin-4-yl)-methanone (80mg, 0.21mmol) and N,N-dimethylsulfamoyl chloride (0.3ml, 2mmol) in pyridine (5ml) was heated to 7O ⁰ C for 16 hours. The reaction was cooled then filtered and the filtrate diluted with dichloromethane (20ml). The resulting solution was washed with hydrochloric acid

2Ν (20ml), the organics collected and dried over magnesium sulfate. The solvent was removed in vacuo and the residue purified by preparative thin layer chromatography eluting with 50% ethylacetate/hexanes to afford the title compound as a colourless oil

(35mg, 35% yield). HPLC retention time β.lmin. Mass spectrum (ES+) m/z 480 (M+H).

Other compounds prepared by Method F as described for example 6 using the appropriate starting materials are listed in TABLE 1.

Example 7) l-Methyl-lH-imidazole-4-sulfonic acid benzyl-[4-(4-methyl-piperazine- l-carbonyl)-phenyl]-amide (Method G)

To a stirred solution of 4-[benzyl-(l-methyl-lH-imidazole-4-sulfonyl)-amino]-benzoic acid (37mg, O.lmmol) in dry dimethylformamide (ImI) was added iV-methylpiperazine

(20mg, 0.2mmol), triethylamine (28μl , 0.2mmol) then 2-(7-aza-lH-benzotriazole-l-yl)-

1,1,3,3-tetramethyluronium hexafluorophosphate (42mg, O.llmmol) and the solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue purified using preparative HPLC to afford the title compound as a clear oil (30mg, 66% yield). HPLC retention time 4.5min. Mass spectrum (ES+) m/z 454

(M+H). Other compounds prepared by Method G as described for example 7 using the appropriate starting materials are listed in TABLE 1.

Example 8) l-Methyl-lH-imidazole-4-sulfonic acid benzyl-[4-(4-phenyl-piperazin-l- yl methyl)-phenyl]-amide (Method H)

i) 4-(4-Phenyl-piperazin-l-yl methyl)-phenylamine

A solution of sodium borohydride (63 mg, 1.68 mmol) in ethanol (1 ml) was added drop- wise to a stirred solution of 4-(4-phenylpiperazine-l-yl methyl)-nitro-aniline (Ig, 3.36 mmol) and tin (II) dichloride dihydrate (2.27 g, 10.10 mmol) in ethanol (20 ml) at 60°C. The resulting solution was stirred for 2h after which the reaction was cooled to O ⁰ C and basified (pH>10) by the addition of sodium hydroxide (2M). The aqueous layer was extracted with dichloromethane (3 x 20ml) and the combined organics washed with brine, then dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (hexanes/ethyl acetate 1:1) to afford the title compound as a pale yellow solid (441 mg, 49%). HPLC retention time 5.82min. Mass spectrum (ES+) m/z 268 (M+H).

H) Benzyl-[4-(4-phenyl-piperazin-l-yl methyl)-phenyl)-amine

Sodium triacetoxyborohydride (282 mg, 1.34 mmol) was added in one portion to a stirred solution of 4-(4-phenyl-piperazin-l-yl methyl)-phenylamine, benzaldehyde (75 μl, 0.73 mmol) and acetic acid (43 μl, 0.73 mmol) in dry dichloromethane (6 ml) and the reaction was stirred for 16 hours at room temperature. Water was added and the organic layer separated then washed with brine and dried over magnesium sulfate. The solution was concentrated in vacuo and the crude residue purified by column chromatography (hexanes/ethyl acetate 1:1) to afford the title compound as a colourless solid (175 mg, 72%). HPLC retention time 7.53min. Mass spectrum (ES+) m/z 358 (M+H).

Hi) l-Methyl-lH-imidazole-4-sulfonic acid benzyl-[4-(4-phenyl-piperazin-l-yl methyl)- phenylj-amide (8) A solution of benzyl-[4-(4-phenyl-piperazin-l-yl methyl)-phenyl)-amine (30 mg, 0.08 mmol), l-methylimidazole-4-sulfonyl chloride (51 mg, 0.27 mmol) and pyridine (24 μl, 0.30 mmol) in dry dichloromethane (2 ml) were heated to reflux for 15 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by column chromatography (5% methanol in dichloromethane) to afford the title compound as an off white solid (22 mg, 55%). HPLC retention time 7.04min. Mass spectrum (ES+) m/z 502 (M+H). ¹ H-NMR (CDCl ₃ ) δ _H 2.54 (4H, m, 2 x CH ₂ ), 3.16 (4H, m, 2 x CH ₂ ), 3.45 (2H, br s, CH ₂ ), 3.71 (3H, s, CH ₃ ), 4.99 (2H, s, CH ₂ ), 6.84 (IH, t, J = 7.3 Hz, ArH), 6.89 (2H, m, 2 x ArH), 7.10 (2H, m, 2 x ArH), 7.17-7.30 (1OH, m, 10 x ArH), 7.55 (IH, m, ArH).

TABLE l

Summary of synthesis methods, characterisation data and biological activity

Example 101 : Kv 1.3 Autopatch Electrophysiology Method

Cells stably transfected with cDNA for human Kvl.3 (in pcDNA3.1) were grown in Ex- cell 302 serum-free medium for CHO cells, supplemented with 10/xl/ml [lOOxj glutamine, 500μg/ml G418 (gentimicin), and 1% HT supplement (5Ox ₇ hypoxanthine and thymidine). Compounds were tested on these cells using the AutoPatch technology in whole cell mode.

The external bathing solution contained (in niM): 150 NaCl, 10 KCl, 1 MgCl ₂ , 3 CaCl ₂ , 10 HEPES, pH 7.4 with NaOH. Patch pipettes were filled with an electrode solution of composition (in mM): 100 K-Gluconate, 20 KCl, 1 MgCl ₂ , 1 CaCl ₂ , 10 HEPES, 11 EGTA, 5 ATP-Na ₂ , 2 Glutathione pH 7.2 with KOH.

Compounds were dissolved in DMSO (100%) and made up in the external bather at a concentration of lμM immediately prior to use. All experiments were conducted at room temperature.

A cell suspension (10ml), with a density of 6x10 ⁶ cells, was aliquoted into a 15ml centrifuge tube and stored at 4°C before use. Prior to use a tube was taken and centrifuged at 1000 rpm for 4 mins at room temperature. The supernatant was then discarded, leaving a cell pellet at the bottom of the tube. The pellet was then resuspended using 1 ml of cold (4°C), filtered (0.22μm), 0.05 % BSA/bather solution (0.05g BSA/lOOml bather). The bottom of the tube was manually agitated followed by gentle tituration. The cell suspension was then placed in the AutoPatch™ temperature controlled cell-hotel at 14°C and regularly titurated.

A length of Teflon capillary tubing was dipped into the cell suspension solution, and a column of fluid was taken up by negative pressure. The column of fluid was in electrically connectivity with a Ag/AgCl reference electrode. Borosilicate glass patch pipettes (from 1.5mm OD, thin- walled filamented, GCl 50-TF capillary glass, Harvard) were pulled using a DMZ pipette puller (Zeitz Instruments), and were back-filled using the internal pipette solution, being careful that no bubbles remained at the tip or in the body of the pipette. Patch pipettes typically had resistances of 2.5-3.5 MΩ. Once filled, the pipette tip and a proportion of the shaft (~ 15mm) were dipped into Sigmacote (Sigma). The recording pipettes were placed in a multiwell array and mounted on the

T1VΪ

AutoPatch machine. Automated patch-clamping and drug-application was initiated by the operator, but thereafter AutoPatch.exe continued the experiment providing that preset conditions and criteria were satisfied.

Whole cell patch-clamp recordings were made using the AutoPatch™ rig, which incorporated an EPC9 or EPClO amplifier (HEKA, Germany) under control of Pulse software (v8.54 or v8.76, HEKA, Germany), a cell applicator, automated drug application system (DAS), valve controller (VFl) and a suction device all at room temperature. This equipment was completely under the control of AutoPatch.exe and operator intervention was only made when there was a requirement to refill the bather reservoirs or to prevent the loss of a cell due to a technical error. Qualification stages prior to perfusion and drug application ensured that the observed current met the criteria for the experiment. Cells were continuously perfused with external solution at a flow rate of ~2 ml/minute. The perfusion chamber had a working volume of 80-85μl that allowed for rapid exchange of drug solutions.

Electrophysiology voltage-step protocols and analysis of data was performed as follows. Data were sampled at 5kHz, and filtered with a -3dB bandwidth of 2.5kHz. Cells were held at a voltage of -8OmV. Currents were evoked by a voltage step to +3OmV for 500ms in duration applied every 15s. Online analysis of the hKvl.3 current during the application of compounds was performed by the Pulse (v8.54 or v8.76, HEKA, Germany), Excel (Microsoft, USA) and AutoPatch™ software, with the total charge measured during the whole of voltage step. Inhibition of charge movement in the presence of drug was calculated relative to control.

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