MXPA06014256A - Furanopyrimidine compounds effective as potassium channel inhibitors. - Google Patents

Abstract

A compound of formula (I) wherein R1 is aryl, heteroaryl, cycloalkyl or alkyl; R2 is H, alkyl, nitro, -CO2R7, CONR4R5 or halo; R3 is H, NR4R5, NC(O)R8, halo, trifluoromethyl, alkyl, nitrile or alkoxy; R4 and R5 may be the same or different, and may be H, alkyl, aryl, heteroaryl or cycloalkyl; or R4 and R5 may together form a saturated, unsaturated or partially saturated 4 to 7 member ring, wherein said ring may optionally comprise one or more further heteroatoms selected from N, O or S; X is O, S or NR6; R6 is H or alkyl; R7 is hydrogen, methyl or ethyl; R8 is methyl or ethyl; Ll is (CH2)n, where n is 1,2 or 3; and Y is aryl, a heterocyclic group, alkyl, alkenyl or cycloalkyl; together with pharmaceutically acceptable salts thereof. The use of these compounds as potassium channel inhibitors is also described.

Description

COMPU THESE OF FU NO-PIRI MIDINA E FECTIVOS LIKE I N HIBI DORES POTASIO CHANNEL The present invention relates to furan-pyrimidine compounds which are inhibitors of the potassium channel. Also provided are pharmaceutical compositions comprising the compounds, and their use in the treatment of arrhythmia. Ion channels are proteins that extend the lipid bilayer of the cell membrane, and provide an aqueous path through which specific ions can pass, such as Na +, K \ Ca2 +, and IC "(Herbert, 1998). Potassium channels represent the largest and most diverse sub-group of ion channels, and have a central role in the regulation of membrane potential and in the control of cell excitability (Armstrong and Hille, 1998). Potassium channels have been categorized into genetic families based on their amino acid sequence and their biophysical properties (for nomenclature, see Gutman et al., 2003).

Compounds that modulate potassium channels have multiple therapeutic applications in several disease areas, including cardiovascular, neuronal, auditory, renal, metabolic, and cell proliferation (Shieh et al., 2000, Ford et al., 2002). More specifically, potassium channels, such as Kv4.3, hERG, KVLQT1 / minK, and Kv1.5, are involved in the repolarization phase of the action potential in cardiac atrial myocytes. These subtypes of the potassium channel have been associated with cardiovascular diseases and disorders, including long QT syndrome, hypertrophy, ventricular fibrillation, and atrial fibrillation, all of which can cause heart failure and fatality (Marban, 2002). The potassium channel subunit with human delayed rectifier voltage gate, Kv1.5, is expressed exclusively in atrial myocytes, and is thought to offer therapeutic opportunities for the management of atrial fibrillation for several different reasons (see the Brendel review). and Peukert, 2002): (i) there is evidence that Kv1.5 underlies the physiological current of the ultra-fast cardiac delayed rectifier (Kv (ur)) in humans, due to its similar biophysical and pharmacological properties (Wang et al., 1993; and Fedida et al., 1993). This has been supported by anti-sense oligonucleotides for Kv1.5, which have been shown to reduce the amplitude of Kv (ur) in human atrial myocytes (Feng et al., 1997). (ii) Electrophysiological records have shown that Kv (ur) is selectively expressed in atrial myocytes, and therefore avoids the induction of potentially fatal ventricular arrhythmias through interference with ventricular repolarization (Amos et al., 1996; Li and collaborators, 1996, and Nattel, 2002). (iii) Inhibition of Kv (ur) in atrial fibrillation-type human atrial myocytes prolonged the duration of the action potential, in comparison with normal healthy human atrial myocytes (Coutermanche et al., 1999). (iv) Prolongation of the action potential duration by selective inhibition of Kv1.5 could offer safer pharmacological interventions to protect against atrial reentrant arrhythmias, such as atrial fibrillation and atrial flutter, compared with antiarrhythmic drugs Class III, through the prolongation of the atrial refractory period, while the ventricular refractory is left unchanged (Nattel et al., 1999, Knobloch et al., 2002, and Wirth et al., 2003). Class III anti-arrhythmics have been widely reported as a preferred method for the treatment of cardiac arrhythmias (Colatsky et al., 1990). It has been reported that traditional and novel class III anti-arrhythmic potassium channel blockers have a mechanism of action through the direct modulation of Kv1.5 or Kv (ur). The known class III anti-arrhythmics, bothilid (Feng et al., 1997), quinidine (Wang et al., 1995), clofilio (Malayev et al., 1995), and bertosamil (Godreau et al., 2002), have all been reported as blockers of the Kv potassium channel. (ur) in human atrial myocytes. The novel benzopyran derivative, NIP-142, blocks the Kv1.5 channels, prolongs the atrial refractory period, and terminates fibrillation and atrial flutter in canine models in vivo (Matsuda et al., 2001), and S9947 inhibited the Kv1.5 stably expressed in both Xenophus oocytes and Chinese hamster ovary (CHO) and Kv (ur) cells in cardiac rat and human cardiac myocytes (Bachmann et al., 2001). Elsewhere, other novel potassium channel modulators targeting Kv1.5 or Kv (ur) have been described for the treatment of cardiac arrhythmias, and these include biphenyls (Peukert et al., 2003), amide Thiophene carboxylic acid (International Publication Number WO0248131), bisaryl derivatives (International Publications Nos. WO0244137 and WO0246162), Carbonamide derivatives (International Publications Nos. WO0100573 and WO0125189), Anthranilic acid amides (International Publications Nos. WO2002100825, WO0208873, and WO02087568) , dihydro-pyrimidines (International Publication Number WO0140231), cycloalkyl derivatives (International Publication Number WO03063797), indane derivatives (International Publications Nos. WO0146155 and WO9804521), tetralin-benzocycloheptane derivatives (International Publication Number WO9937607), thiazolidone and metathiazanone derivatives (International Publication Number WO) 9962891), benzamide derivatives (International Publication Number WO0025774), isoquinoline derivatives (International Publication Number WO0224655), pyridazinone derivatives (International Publications Nos. WO9818475 and WO9818476), chroman derivatives (International Publication Number WO9804542), benzopyran derivatives (Publications International Nos. WO0121610, WO03000675, WO0121609, WO0125224, and WOQ2064581), benzoxazine derivatives (International Publication Number WO0012492), and the novel compound A1998 purified from Ocean material (Xu and Xu, 2000). Several additional publications disclose compounds that are indicated by acting on potassium channels. Accordingly, U.S. Patent No. US6531495 discloses 2'-amino-methyl-biphenyl-2-carboxamides, International Publication Number WO2002 / 100825 discloses anthranilic acid amides as anti-arrhythmic, and International Publication Number WO2002 / 036556 discloses acyl-amino-alkyl-benzenesulfonamides as cardiovascular agents. It has been reported that furan-pyrimidines are useful as inhibitors of folate, anti-histamines, muscle relaxants, and agrochemicals. Furan-pyrimidines have not previously been reported as useful agents for modulating ion channels. The synthesis of different 4-amino-substituted furan-pyrimidines has been reported (Antonov et al., 1994), as well as certain 4-benzyl-amino-substituted furan-pyrimidines (Belenki et al., 1993). Furano-pyrimidines substituted in the 5-position with an alkyl group have been identified as pesticides and fungicides. Accordingly, European Patent Number EP459611 discloses a family of 4-phenyl-ethyl derivatives, while European Patent Number EP196526 discloses a series of 4-phenoxy-propyl derivatives. It has also been reported that furane-pyrimidines substituted with an alkyl group in the 5-position have a muscle relaxant activity (Japanese Patent Number JP48081893 and German Patent Number DE1817146). This invention provides compounds that are inhibitors of the potassium channel. In a specific manner, furan-pyrimidines with an aromatic or heteroaromatic substituent in the 5-position are disclosed. These compounds are particularly useful for inhibiting Kv1.5 or Kv potassium channels (ur), which are known targets for the treatment of cardiac arrhythmia in the atrium, such as atrial fibrillation (Nattel et al., 1999; Wang et al., 1993). This invention is not limited to the treatment of cardiac arrhythmias, the compounds also being useful for treating other diseases that require inhibition of the potassium channel (eg, Shieh et al., 2002; Ford et al., 2002). Accordingly, in a first aspect, the present invention provides a compound of Formula I: where: R 1 is aryl, heteroaryl, cycloalkyl, or alkyou; R 2 is H, alk uyl, nitro, -C0 2 R 7, CON R 4 R 5, or halogen; R 3 is H, N R 4 R 5, N C (O) R 8, halogen, trifluoromethyl, alkyl, nitrile, or alkoxy; R4 and R5 may be the same or different, and may be H, alkyl, aryl, heteroaryl, or cycloalkyl; or R4 and R5 may together form a saturated, unsaturated, or partially saturated 4- to 7-membered ring, wherein this ring may optionally comprise one or more additional heteroatoms selected from N, O, or S; X is Q, S, or N R6; R6 is H or alkyl; R7 is hydrogen, methyl, or ethyl; R8 is methyl or ethyl; L is (CH2) n, where n is 1, 2, or 3; and Y is aryl, a heterocyclic group, alkyl, alkenyl, or cycloalkyl; or pharmaceutically acceptable salts thereof. As used herein, an alkyl group or moiety is typically a linear or branched alkyl group or moiety containing 1 to 6 carbon atoms, such as an alkyl group or moiety of 1 to 4 carbon atoms. , for example methyl, ethyl, normal propyl, isopropyl, butyl, isobutyl, and tertiary butyl. An alkyl group or fraction may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries 1 or 2 substituents. Suitable substituents include halogen, cyano, nitro, NR9R10, alkoxy, hydroxyl, unsubstituted aryl, unsubstituted heteroaryl, C02R7, C (O) NR9R10, NC (O) R8, and SO2NR9R10. As used herein, an aryl group is typically an aryl group of 6 to 10 carbon atoms, such as phenyl or naphthyl. A preferred aryl group is phenyl. An aryl group may be unsubstituted or substituted at any position. Typically, it carries 1, 2, 3, or 4 substituents. Suitable substituents include cyano, halogen, trifluoromethyl, alkyl, thioalkyl, alkoxy, NR9R10, CO2R7, C (O) NR9R10, NC (O) R8, and SO2NR9R10, and hydroxyl. As used herein, a heterocyclic group is a heteroaryl group, typically a 5- to 10-membered aromatic ring, such as a 5- or 6-membered ring, containing at least one heteroatom selected from O, S, and N. Examples include the pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, and pyrazolyl groups. Preferred heteroaryl groups are furanyl, thieno, and pyridyl. Examples of polycyclic heterocycles include indolyl, benzofuranyl, benzothiophenyl, and benzodioxolyl. Also included are heterocyclic groups other than aryl, such as tetrahydrofuranyl or pyrrolidinyl. A heterocyclic group may be unsubstituted or substituted at any position. Suitable substituents include cyano, nitro, halogen, alkyl, thioalkyl, alkoxy, NR9R10, CO2R7, C (O) NR9R10, NC (O) R8, and SO2NR9R10, and hydroxyl.

R9 and R10 may be the same or different, and may be selected from H, unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl, amino-ethyl, methyl-amino-ethyl, dimethyl-amino-ethyl, hydroxy-ethyl, alkoxyethyl, or R9 and R10 may together form a saturated, unsaturated, or partially saturated 4 to 7 membered ring. When R4 and R5 or R9 and R10 together form a saturated, unsaturated, or partially saturated 4- to 7-membered ring, the ring may optionally comprise 1, 2, or 3 additional heteroatoms. As used herein, "alkoxy" means alkoxy from 1 to 3 carbon atoms; cycloalkyl means cycloalkyl of 3 to 6 carbon atoms; and halogen means Cl, F, Br, or I, preferably Cl, F, or Br. Preferred compounds of Formula I are those wherein R 1 is aryl or heteroaryl, R 2 is H or alkyl, R 3 is H, NR 4 R 5, alkoxy, or alkyl; X is O or NR6, R6 is H, n is 1 or 2, and Y is alkyl, cycloalkyl, aryl, or heteroaryl. The most preferred compounds of Formula I are those wherein R 1 is aryl or heteroaryl, R 2 is H or methyl, R 3 is H, NR 4 R 5, alkoxy, or alkyl; X is NR6, R6 is H, n is 1, and Y is aryl or heteroaryl. Preferably, Y is phenyl, furanyl, thienyl, or pyridyl. More preferably, Y is optionally substituted phenyl, furan-2-yl, or pyridin-2-yl. Preferred compounds include: 5-phenyl-N- (pyridin-2'-yl-methyl) -furo- [2,3-d] -pyrimidin-4-amine, 5- (4-chloro-phenyl) -N- (pyrid n-2'-yl-m eti l) -furo- [2, 3-d] -pyrim id-n-4-amine, 6-methyl-5-phenyl-N- ( pyridin-2'-yl-methyl) -furo- [2,3-d] -pyrimidin-4-amine, (2-morpholin-4-yl-5-phenyl-furo- [2,3-d] -pyrimidin -4-yl) -pyridin-2-yl-methyl-amine; 2 - ((2-idroxy-ethyl) -. {5-phenyl-4 - [(pyridin-2-yl-methyl) -amino] -furo- [2,3-d] -pyrimidin-2-yl} -amino) -ethanol, 2 - ((2-hydroxy-ethyl) -. {5- (4-fluoro-phenyl) -4 - [(pyridin-2-yl-methyl) -amino] -furo- [2,3-d] -pyrimidin-2-yl.}. -amino) -ethanol, N 2 - (2-methoxy-ethyl) -5-phenyl-N 4 -pyridin-2-yl-methyl-furo- [2 , 3-d] -pi rim id in-2, 4-d amine, 2-. { 5-phenyl-4 - [(pyridin-2-yl-methyl) -amino] -furo- [2,3-d] -pyrimidin-2-yl-amino} -propan-1,3-diol, N2, N2-dimethyl-5-phenyl-N4-pyridin-2-yl-methyl-furo- [2,3-d] -pyrimidine-2,4-diamine, N2, N2 -dimethyl-N 4 - (6-methyl-pyridin-2-yl-methyl) -5-phenyl-furo- [2,3-d] -pyrimidine-2,4-diamine, or [2- (2-methoxy) ethoxy) -5-phenyl-furo- [2,3-d] -pyrimidin-4-yl] -pyridin-2-yl-methyl-amine; and pharmaceutically acceptable salts thereof. The compounds of Formula I wherein R3 = H, are conveniently synthesized from a compound of Formula II by reaction with a suitable nucleophile HX-LY (wherein X, Y, and L are as defined herein) ), optionally in the presence of a solvent, and optionally at elevated temperature. Preferably, the solvent (if present) is an alcohol, preferably ethanol. If a solvent is present, the reaction is carried out at the reflux temperature of the solvent. Or, optionally, the reaction can be carried out in a microwave reactor.

A compound of Formula I I can be obtained from a compound of Formula I I, by reaction with a trialky ortho-formate, in a suitable solvent or without solvent, and with heating. Preferably, the trialkyl orfo-format is triethyl ortho-formate. Preferably, a solvent is present. Suitable solvents include acetic anhydride. When a solvent is present, the reaction is carried out at the reflux temperature.

The compounds of Formula I I I can be obtained by the reaction of a compound of Formula IV with malononitrile. The reaction can be carried out in the presence of a suitable solvent and a base. Preferably, the solvent is ethanol, and the reaction is carried out under reflux conditions. In a preferable way, a base is present. The appropriate bases include the organic mimics, such as triethyl-amn a. R.sup.2 R.sup.2 OH A compound of the formula IV can be prepared by the reaction of a compound of the formula V under oxidation conditions. Preferred oxidizing agents include [bis- (trifluoro-acetoxy) -iodo] -benzene. The preferred reaction is carried out in the presence of a solvent and an organic acid. Suitable solvents include acetonitrile. Suitable organic acids include trifluoroacetic acid. When a solvent is present, the reaction is carried out at the reflux temperature.

In an alternative synthesis of the compounds of Formula I, particularly applicable when R3 is a substituent other than H, a suitable nucleophile R3H is reacted with a compound of Formula VI. Preferably, the reaction is carried out in the presence of a base and a solvent. Optionally, the reaction can be carried out in a microwave reactor.

A compound of Formula VI is conveniently prepared from a compound of Formula VII. Suitable reaction conditions include the use of a nucleophile HX-L-Y in the presence of a base and a solvent. Preferably, the base is a hindered organic amine base, such as triethylamine, and the solvent is an alcohol such as ethanol.

A compound of Formula VII can be prepared by oxidation of a compound of Formula VIII. Suitable conditions include the use of a peroxide reactant in an organic acid. Preferably, the peroxide reactant is hydrogen peroxide, and the organic acid is acetic acid.

A compound of Formula VIII can be prepared by the reaction of a compound of Formula IX under alkylation conditions. Suitable conditions include the use of a methyl iodide, under basic conditions. Preferably, the basic conditions comprise a metal hydroxide mixed with an alcohol and water. Preferably, the alcohol is ethanol, the metal hydroxide is potassium hydroxide, and the alkyl halide is methyl iodide.

A compound of Formula IX can be prepared in a convenient manner by reacting a compound of Formula I I I with potassium ethyl xanthate. Preferably, the reaction is carried out in alcohol. Preferably, the alcohol is butanol. In a further method, particularly applicable for the examples wherein R3 is a functionalized alkyl substituent, a compound of Formula X is reacted with a suitable nucleophile HX-L-Y. The reaction is carried out in the presence of a base and in n solvent. The base is preferably an organic amine base, such as triethylamine, and the solvent is preferably an alcohol such as ethanol. The reaction is carried out at the reflux temperature of the solvent. In an alternative way, the reaction can be carried out with microwave heating.

A compound of Formula X can be prepared by reacting a compound of Formula XI with a suitable chlorinating reagent. Preferably, the chlorination reagent is thionyl chloride, phosphorus oxychloride, or diphenyl phosphinic chloride. Preferably, the reaction is carried out in the presence of a base, such as an amine base. Preferred bases include triethylamine and diethylamine. Optionally, the base can also serve as the solvent. The reaction is carried out at 60 ° C to 100 ° C.

The compounds of Formula XI can be prepared by the reaction of a compound of Formula XII under acidic conditions in a solvent. Preferably, the acid is an inorganic acid, such as hydrochloric acid, and the solvent is an organic solvent, such as dioxane. The reaction is carried out at or below the reflux temperature of the solvent.

The compounds of Formula XII are readily prepared from the compounds of Formula III by reaction with ethyl malonyl chloride. Preferably, the reaction is carried out with cooling and in the presence of a base and an organic solvent. Preferably, the base is triethylamine, and the solvent is tetrahydrofuran, and the reaction is carried out below 5 ° C. It is understood that the compounds of Formula I wherein R3 is a carboethoxy group, can undergo transformation of the functional group of the ester moiety using methods familiar to those skilled in the art. In a preferred case, these compounds can be amidated by their reaction with an alkyl or a dialkyl amine. In another preferred case, the compounds of Formula I wherein R3 is a 1-hydroxyethyl group, can be prepared by reaction with a reducing agent, such as di-isobutyl aluminum hydride, or lithium aluminum hydride. . In a further case, the compounds of Formula I wherein R3 is a carboethoxy group, can be reacted with a dialkyl carbonate under basic conditions, to provide a compound of Formula I wherein R3 is a dialkyl malonyl group. These compounds can be reduced, preferably with a reducing agent, such as di-isobutyl aluminum hydride or lithium aluminum hydride, to provide the compounds of the Formula | wherein R3 is a propanediol group. Many of the starting materials referred to in the reactions described above are available from commercial sources, and can be made by the methods cited in literature references. Synthetic methods can also be found in reviews; thiophenes, for example, can be found in the references cited in Comprehensive Heterocyclic Chemistry, Editors Katritzky, AR, Rees, CR, (4), 863-934, and Comprehensive Heterocyclic Chemistry (II), Editors Katritzky, AR, Rees, CW, Scriven, EFV, (2), 607-678. Suitable starting materials include: As discussed herein, the compounds of the invention are useful in the treatment of different conditions. Accordingly, in a second aspect, the present invention provides a pharmaceutical formulation comprising at least one compound of the invention and optionally one or more excipients, carriers or diluents, wherein this compound has the Formula: wherein: R1 is aryl, heteroaryl, cycloalkyl, or alkyl; 2 is H, alkyl, nitro, -CO2R7, CONR4R5, or halogen; R3 is H, NR4R5, NC (O) R8, halogen, trifluoromethyl, alkyl, nitrile, or alkoxy; R4 and R5 may be the same or different, and may be H, alkyl, aryl, heteroaryl, or cycloalkyl; or R4 and R5 may together form a saturated, unsaturated, or partially saturated 4- to 7-membered ring, wherein this ring may optionally comprise one or more additional heteroatoms selected from N, O, or S; X is O, S, or NR6; R6 is H or alkyl; R7 is hydrogen, methyl, or ethyl; R8 is methyl or ethyl; L is (CH2) n, where n is 1, 2, or 3; and Y is aryl, a heterocyclic group, alkyl, alkenyl, or cycloalkyl; or pharmaceutically acceptable salts thereof. The compositions of the invention may be presented in unit dosage forms containing a predetermined amount of each active ingredient per dose. This unit can be adapted to provide 5 to 100 milligrams / day of the compound, preferably 5 to 15 milligrams / day, 10 to 30 milligrams / day of 25 to 50 milligrams / day., from 40 to 80 milligrams / day, or from 60 to 100 milligrams / day. For the compounds of Formula I, doses in the range of 100 to 1,000 milligrams / day, preferably 100 to 400 milligrams / day, 300 to 600 milligrams / day, or 500 to 1,000 milligrams / day are provided. These doses may be provided in a single dose or as a number of separate doses. Of course, the final 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 discretion of the doctor. The compositions of the invention can be adapted for administration by any appropriate route, for example orally (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal). These formulations can be prepared by any method known in the pharmacy art, for example by associating the active ingredient with the carriers or excipients. Pharmaceutical formulations suitable for oral administration may be presented as separate units, such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams; or liquid emulsions of oil in water or liquid emulsions of water in oil. Pharmaceutical formulations suitable for transdermal administration may be presented as separate patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient can be delivered from the patch by iontophoresis, as generally described in Pharmaceutical Research, 3 (6), 318 (1986). Pharmaceutical formulations suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. For applications to the eye or to other external tissues, for example to the mouth and to the skin, the formulations are preferably applied as an ointment or topical cream. When formulated in an ointment, the active ingredient can be used with either a paraffinic ointment base or water miscible. Alternatively, the active ingredient can be formulated in a cream with an oil-in-water cream base, or a water-in-oil base.

Pharmaceutical formulations suitable for topical administration to the eye include eye drops, wherein the active ingredient is dissolved or suspended in a suitable vehicle, especially an aqueous solvent. Pharmaceutical formulations suitable for topical administration in the mouth include dragees, lozenges, and mouth rinses. Pharmaceutical formulations suitable for rectal administration can be presented as suppositories or enemas. Pharmaceutical formulations suitable for nasal administration, wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of 20 to 500 microns, which is administered in the manner in which it is administered. take an aspiration, for example by rapid inhalation through the nasal passage from a container of dust held close to the nose. Suitable formulations wherein the vehicle is a liquid, to be administered as a nasal spray, or as nasal drops, include aqueous or oily solutions of the active ingredient. Pharmaceutical formulations suitable for administration by inhalation include powders in fine particles or mists, which can be generated by means of different types of aerosols, nebulizers, or pressurized insufflators with metered doses. Pharmaceutical formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or aerosol formulations.

Pharmaceutical formulations suitable for parenteral administration include sterile aqueous and non-aqueous injection solutions, which may contain anti-oxidants, pH regulators, 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 viscosifying agents. The formulations can be presented in single-dose or multi-dose containers, for example sealed vials and flasks, and can be stored in a freeze-dried (lyophilized) condition, which requires only the addition of the sterile liquid carrier, for example water for injection, immediately before use. Solutions and suspensions for extemporaneous injection can be prepared from sterile powders, granules, and tablets. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as mentioned hereinbefore, 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 flavoring agents.

In a further aspect, the present invention provides a compound, or a pharmaceutical composition comprising this compound, for use in medicine, wherein the compound has the Formula: wherein: R1 is aryl, heteroaryl, cycloalkyl, or alkyl; R2 is H, alkyl, nitro, -C02R7, CONR4R5, or halogen; R3 is H, NR4R5, NC (O) R8, halogen, trifluoromethyl, alkyl, nitrile, or alkoxy; R4 and R5 may be the same or different, and may be H, alkyl, aryl, heteroaryl, or cycloalkyl; or R4 and R5 may together form a saturated, unsaturated, or partially saturated 4- to 7-membered ring, wherein this ring may optionally comprise one or more additional heteroatoms selected from N, O, or S; X is O, S, or NR6; R6 is H or alkyl; R7 is hydrogen, methyl, or ethyl; R8 is methyl or ethyl; L is (CH2) n, where n is 1, 2, or 3; and Y is aryl, a heterocyclic group, alkyl, alkenyl, or cycloalkyl; or pharmaceutically acceptable salts thereof. Preferably, the compound is a compound of the first aspect. The compositions of the invention can be used to treat conditions that require the inhibition of potassium channels, for example in the treatment of arrhythmia. Accordingly, in the additional aspects, the present invention provides: (i) A method for the treatment or prevention of a disorder requiring the inhibition of the potassium channel, for example arrhythmia, which comprises administering to a subject an amount effective of at least one compound or of a pharmaceutical composition comprising at least one compound, and optionally one or more excipients, diluents, and / or carriers, wherein this compound has the Formula: wherein: R1 is aryl, heteroaryl, cycloalkyl, or alkyl; R2 is H, alkyl, nitro, -C02R7, CONR4R5, or halogen; R3 is H, NR4R5, NC (O) R8, halogen, trifluoromethyl, alkyl, nitrile, or alkoxy; R4 and R5 may be the same or different, and may be H, alkyl, aryl, heteroaryl, or cycloalkyl; or R4 and R5 may together form a saturated, unsaturated, or partially saturated 4 to 7 membered ring, wherein this ring may optionally comprise one or more additional heteroatoms selected from N, O, or S; X is O, S, or NR6; R6 is H or alkyl; R7 is hydrogen, methyl, or ethyl; R8 is methyl or ethyl; L is (CH2) n, where n is 1, 2, or 3; and Y is aryl, a heterocyclic group, alkyl, alkenyl, or cycloalkyl; or pharmaceutically acceptable salts thereof; and (ii) The use of a compound of the invention in the manufacture of a medicament for use in the inhibition of the potassium channel, wherein the compound has the Formula: wherein: R1 is aryl, heteroaryl, cycloalkyl, or alkyl; R2 is H, alkyl, nitro, -CO2R7, CONR4R5, or halogen; R3 is H, NR4R5, NC (O) R8, halogen, trifluoromethyl, alkyl, nitrile, or alkoxy; R4 and R5 may be identical or different, and may be H, alkyl, aryl, heteroaryl, or cycloalkyl; or R4 and R5 may together form a saturated, unsaturated, or partially saturated 4- to 7-membered ring, wherein this ring may optionally comprise one or more additional heteroatoms selected from N, O, or S; X is O, S, or NR6; R6 is H or alkyl; R7 is hydrogen, methyl, or ethyl; R8 is methyl or ethyl; L is (CH2) ", where n is 1, 2, or 3; and Y is aryl, a heterocyclic group, alkyl, alkenyl, or cycloalkyl; or pharmaceutically acceptable salts thereof. In particular, the medicament is for use in the treatment or in the prevention of arrhythmia. Preferably, the compounds are the compounds of the first aspect. Examples Using the information illustrated herein, the following compounds can be synthesized, which are given by way of example only. The pharmacological profile of the compounds of the present invention can be readily evaluated by those skilled in the art, employing routine experimentation, such as the methods and techniques illustrated herein and described in detail in Ford et al., 2002.

Example 1 1- (4-Fluoro-phenyl) -2-hydroxy-ethanone Under a nitrogen atmosphere, a stirred solution of 4'-fluoro-acetophenone (1.5 grams, 8.32 mmol) in acetonitrile (42 milliliters) was treated with [bis- (trifluoro-acetoxy) -yodo] -benzene (7.16 grams, 16.6 millimoles), followed by water (8.3 milliliters) and trifluoroacetic acid (1.3 milliliters). The resulting solution was heated under reflux for 2 hours before standing overnight at room temperature. The solvent was then removed in vacuo; Ag ua (30 milliliters) was added, and the mixture was extracted with dichloromethane (30 milliliters, three times). The combined extracts were washed with a saturated solution of sodium hydrogen carbonate (30 milliliters), followed by brine (30 milliliters), and dried (MgSO4). The solvent was removed in vacuo to give crude 1- (4-fluoro-phenyl) -2-hydroxy-ethanone, which was purified by flash chromatography (silica) eluting with ethyl acetate and 40 ° petroleum ether. C at 60 ° C (3: 1), to give a white solid (0.55 grams). Examples 2 to 7 The compounds set forth below were prepared in the same manner as in Example 1, using the appropriate starting materials.

Eiem plo 8 2-am i no-4- (4-fluoro-phenyl) -3-furonitrile A solution of malononitrile (0.31 g bouquets, 4.65 millimoles) and triethylamine (0.65 milliliters, 4.65 millimoles) in methanol (5 milliliters) was added dropwise to a stirred suspension of 2-hydroxy-4'-fluoro-acetophenone (0.65 grams, 4.22 mmol) in methanol (16 milliliters) under a nitrogen atmosphere at room temperature. When the ad ición was finished, the mixture was stirred for 1 8 hours at room temperature. Then the solvent was removed under vacuum, then water (50 milliliters) was added to the residue, and the mixture was extracted with dichloromethane (50 milliliters, three times). The combined extracts were dried (MgSO4), and the solvent was removed under vacuum, to give the crude 2-amino-4- (4'-fluoro-phenyl) -3-furonitrile, which was partially purified by flash chromatography. (silica), eluting with dichloromethane and ethyl acetate (1: 1). This gave a 3.5: 1 mixture of the product and 2-hydroxy-4'-fluoro-acetophenone (0.60 grams), which was used without further purification.

Examples 9 to 1 3 The compounds stipulated in sec ond were prepared in the same manner as in Example 8, using the appropriate starting materials.

Example 1 5 3-cyano-4- (4-fluoro-phenyl) -2-furyl-imido-ethyl formate A stirred mixture of 2-amino-4- (4-fluoro-phenyl) -3-furonitrile (0.27 grams) , 1.36 millimoles) and orfo-triethyl formate (0.95 milliliters), treated with acetic anhydride (0.65 milliliters), and then heated under reflux for 4 hours. The solvents were then removed in vacuo to give the 3-cyano-4- (4-fluoro-phenyl) -2-furyl-imido-ethyl formate as a brown solid (0.35 grams), which was used without further purification . Examples 1 6 to 20 The compounds set forth below were prepared in the same manner as in Example 15, using the appropriate starting materials.

Example 21 5- (4-Fluoro-phenyl) -N- (pyridin-2-yl-methyl) -furo- [2,3-d] -pipmidin-4-amine A stirred reaction mixture of 3-cyano-4 - (4-fluoro-phenyl) -2-furyl-imido-crude ethyl form (0.35 grams, 1.36 mmol) and pyridin-2-yl-methyl-amine (0.16 milliliters, 1.50 mmol) in ethanol (3.5 milliliters) are heated under reflux for 4 hours. The resulting mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica), eluting with ethyl acetate and dichloromethane (1: 1), to give 5- (4-fluoro-phenyl) -N- (pyridin-2-yl- methyl) -furo- [2,3-d] -pyrimidin-4-amine (0.115 grams) as a grayish solid, p. F. 162 ° C-164 ° C.

Examples 22 to 26 The compounds set forth below were prepared in the same manner as in Example 21, using the appropriate starting materials.

Example 27 5-phenyl-1 H-furo- [2,3-d] -pyrimidine-2,4-dithione A stirred mixture of 2-amino-4-phenyl-furan-3-carbonitrile (5.0 grams, 0.027 moles) and potassium ethyl-xanthate (4.5 grams, 0.027 moles) in butan-1 -ol (25 milliliters) was heated for 2 hours at 1 10 ° C. After cooling to room temperature, the solid was filtered, washed with a little butan-1-ol, and dissolved in water (1000 milliliters). Then the solution was acidified with glacial acetic acid, to give a light brown precipitate. This was filtered, washed with water, and dried under vacuum, to give crude 5-phenyl-1 H -furo- [2,3-d] -pyrimidine-2,4-dithione (3.0 grams), which It was used without further purification. Example 28 to 29 The compounds set forth below were prepared in the same manner as in Example 27, using the appropriate starting materials.

Example 30 2,4-bis-methyl-sulfanyl-5-phenyl-furo- [2,3-d] -pyrimidine A stirred mixture of 5-phenyl-1 H-furo- [2,3-d] -pyrimidine -2,4-dithione (3.0 grams, 0.012 moles) in ethanol (100 milliliters) and potassium hydroxide (1.4 grams, 0.024 moles) in water (25 milliliters), was treated with iodine-methane (3.6 grams, 1.6 milliliters, 0.025 moles). After 3 hours at room temperature, the mixture was diluted with water (250 milliliters), and extracted with dichloromethane (100 milliliters, three times). The combined extracts were dried (MgSO4), and the solvent was removed in vacuo, to give the crude 2,4-bis-methyl-sulfanyl-5-phenyl-furo- [2,3-d] -pyrimidine, which was purified by flash chromatography (silica), eluting with dichloromethane, to give a brown solid (3.0 grams). Examples 31 to 32 The compounds set forth below were prepared in the same manner as in Example 30, using the appropriate starting materials.

Example 33 2, 4-bis-methyl-sulfonyl-l-5-phenyl-furo- [2,3-d] -pyrimidine A stirred suspension of 2,4-bis-methyl-sulfanyl-5-phenyl-furo- [ 2,3-d] -pyrimidine (1.5 grams, 5.21 mmol) in glacial acetic acid (15 milliliters), was treated with hydrogen peroxide (3.6 milliliters of a 27.5 percent aqueous solution, 33.3 millimoles). After 2 hours at room temperature, the mixture was heated to obtain a homogeneous solution, and then stirred at room temperature for 18 hours. Then the reaction mixture was diluted with water (50 milliliters), and extracted with dichloromethane (50 milliliters, three times). The combined extracts were washed with an aqueous solution of sodium metabisulfite (50 milliliters, twice), followed by saturated aqueous sodium acid carbonate (50 milliliters), before drying (MgSO). The solvent was removed in vacuo to give crude 2,4-bis-methyl-sulfonyl-5-phenyl-[2,3-d] -pyrimidine, which was purified by flash chromatography (silica) eluting with ethyl acetate, to give a white solid (0.5 grams).

Examples 34 to 35 The compounds set forth below were prepared in the same manner as in Example 33, using the appropriate starting materials.

Example 36 (2-methansulfonyl-5-phenyl-furo- [2,3-d] -pyrimidin-4-yl) -pyridin-2-yl-methyl-amine A mixture of 2,4-bis-methyl -sulfonyl-5-phenyl-furo- [2,3-d] -pyrimidine (54 milligrams, 0.153 millimoles), triethylamine (17 milligrams, 0.168 millimoles), and 2- (amino-methyl) -pyridine (18 milligrams) , 0.168 mmol) in propan-2-ol (5 milliliters), heated to obtain a solution, and stirred at room temperature for 2.5 hours. Then water (50 milliliters) was added, and the mixture was extracted with dichloromethane (30 milliliters, three times). The combined extracts were dried (MgSO4), and the solvent was removed in vacuo, to give (2-methansulfonyl-5-phenyl-furo- [2,3-d] -pyrimidin-4-yl) -pyridin- Crude 2-yl-methyl-amine, which was purified by flash chromatography (silica), eluting with petroleum ether from 40 ° C to 60 ° C, followed by ethyl acetate, to give a white solid (17 milligrams) ), p. F. 171-173 ° C. Examples 37 to 40 The compounds set forth below were prepared in the same manner as in Example 36, using the appropriate starting materials. d] -pyrimidin-4-yl] -pyridin-2-yl-methyl-amine Example 41 N2- (2-methoxy-ethyl) -5-phenyl-N4-pyridin-2-yl-methyl-furo- [2,3-d] -pyrimidin-2,4-d-amine A stirred mixture of (2-methansulfonyl-5-phenyl-furo- [2,3-d] -pyrimidin-4-yl) -pyridin-2-yl-methylamine (50 milligrams, 0.1 32 mmol), triethylamine (1.5 milligrams, 0.145 mmol), and 2-methoxy-ethyl-amine (1.0 milligrams, 0.197 milli moles) in ethanol (1 milliliter) was heated by microwave irradiation at 1 80 ° C. for 30 minutes. The resulting solution was diluted with water (30 milliliters), and extracted with dichloromethane (30 milliliters, three times). The combined extracts were dried (MgSO4), and the solvent was removed in vacuo, to give the N2- (2-methoxy-ethyl) -5-phenyl-N4-pi-ridin-2-yl-methyl-furo- [2, 3-d] -pyrimidine-2,4-diamine crude, which was purified by flash chromatography (silica), eluting with dichloromethane, followed by ethyl acetate and dichloromethane (2: 1), to give a grayish solid (26 milligrams), p. F. 96-98 ° C. Example 42 to 45 The compounds set forth below were prepared in the same manner as in Example 41, using the appropriate starting materials.

Compound Example 42 (2-morpholin-4-yl-5-phenyl-furo- [2,3-d] -pyrimidin-4-yl) - Eiem plo 46 N2, N2-dimethyl-5-phenyl-N4-pyridin-2-yl-methyl-l-furo- [2,3-d] -pyrimidine-2,4-diamine Ethanol (1 ml) was saturated with dimethylamine, and (2-methansulfonyl-5-phenyl-furo- [2,3-d] -pyrimidin-4-yl) -pi-ridin-2-yl-methyl-amine (50 milligrams, 0.1 32 millimoles). The mixture was then stirred and heated by microwave irradiation at a pressure of 1 7.5 kg / cm2 for 30 minutes, reaching a maximum temperature of 1 38 ° C. The resulting solution was then diluted with water (50 milliliters), and extracted with dichloromethane (5Q milliliters, three times). The combined extracts were dried (MgSO4), and the solvent was removed in vacuo, to give the N2, N2-dimethyl-5-phenyl-N4-pyridin-2-yl-methyl-furo- [2,3-d] - pyrimidine-2,4-diamine crud a, which was purified by flash chromatography (silica), eluting with dichloromethane, followed by dichloromethane and ethyl acetate (9: 1), to give a grayish solid ( 1 9 milligrams), p. F. 1 08- 1 1 0 ° C. Examples 47 to 50 The compounds set forth below were prepared in the same manner as in Example 45, using the appropriate starting materials.

Eiem plo 51 [2- (2-methoxy-ethoxy) -5-phenyl-furo- [2,3-d] -pyrim idin-4-yl] -pi-ridin-2-yl-methyl-amine 2-methoxy - stirred ethanol (1 milliliter) was treated with 60 percent sodium hydride (10 milligrams) followed, after 10 minutes, by (2-methansulfonyl-5-phenyl-furo- [2,3-d] ] -pyrimidin-4-yl) -pyridin-2-yl-methyl-amine (50 milligrams, 0.132 mmol), and was heated by microwave irradiation for 30 minutes at 150 ° C. Then the resulting solution was diluted with water (50 milliliters), and extracted with dichloro-methane (50 milliliters, three times). The combined extracts were dried (M g S O 4), and the solvent was removed in vacuo, to give [2- (2-methoxy-ethoxy) -5-phenyl-furo- [2,3-d] -pyrimidine. 4-yl] -pyridin-2-yl-methyl-amine, which was purified by flash chromatography (silica), eluting with petroleum ether from 40 ° C to 60 ° C, followed by petroleum ether 40 ° C to 60 ° C and ethyl acetate (1: 1), to give a grayish solid (30 milligrams), p. F. 97-99 ° C. Example 3 3 - [(3-Cyano-4-pheyl-2-furyl) -amno] -3-oxo-propanoate ethyl Ethyl malonyl chloride (3.8 milliliters, 29.89 mmol) was added dropwise to a solution of 2-amino-4-phenyl-3-furonitrile (5 grams, 27. 1 7 mmol) and triethylamine (4.2 milliliters, 29.89 mmol) in tetrahydrofuran (30 milliliters), keeping the temperature below 5 ° C low nitrogen. This was allowed to warm to room temperature, and stirred for 2 hours. The reaction mixture was diluted with water, and extracted with dichloromethane. The organic layers were combined and washed with brine, and dried over MgSO4. The solution was filtered, and the solvent was removed under a reddish pressure. The residue was purified by column chromatography using dichloromethane, isolating an orange oil (3.7 grams, 46 percent). Eiem plo 53 (4-oxo-5-phenyl-3,4-dihydro-furo- [2,3-d] -pyrim idin-2-yl) -acetic acid ethyl ester. 3 - [(3-cyano- 4-phenyl-2-furyl) -amino] -3-oxo-propanoate (1.2 grams, 4.2 mmol) to a solution of 4M hydrogen chloride in dioxane (20 milliliters), and was heated to reflux with stirring for 2 hours. The reaction mixture was cooled to room temperature, and poured into a saturated solution of sodium hydrogen carbonate. The aqueous phase was extracted with dichloromethane. The organic phases were combined and washed with brine, and dried over MgSO4. The organic layer was filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography using dichloromethane to give a brown solid (0.925 grams). Example 54 (4-chloro-5-phenyl-furo- [2,3-d] -pyrimidin-2-yl) -acetic acid ethyl ester (4-oxo-5-phenyl-3,4-dihydro-furo- [2,3-d] -pyrimidin-2-yl) -acetic acid ethyl ester (827 milligrams, 2.79 mmol) to a solution of phosphorus oxychloride (13 milliliters, 139.5 millimoles) and diethyl-aniline (4.4 milliliters, 27.8 millimoles) , and warmed to 65 ° C, and stirred for 2.5 hours. The phosphorus oxychloride was removed under reduced pressure, and the residue was diluted with dichloromethane. The organic layer was washed with water twice, then with a saturated solution of sodium hydrogen carbonate, and finally with brine. The solution was dried over MgSO4, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (from 20 to 100 percent dichloromethane / petroleum ether from 40 ° C to 60 ° C), to give an orange oil (100 milligrams).

Example 55 { 5-phenyl-4 - [(pyridin-2-yl-methyl) -ami no] -furo- [2,3-d] -pyrim id in-2-yl} ethyl acetate 2-Amino-methyl-pyridine (36 microliters, 0.347 mmol) was added to a solution of (4-chloro-5-phenyl-furo- [2,3-d] -pyrimidin-2-yl) - ethyl acetate (1 00 milligrams, 0.316 mmol) and triethylamine (48 microliters, 0.347 mmol) in ethanol (5 milliliters), and heated at reflux for 4 hours. The reaction mixture was cooled and diluted with water. The aqueous mixture was extracted three times with dichloromethane. The organic phases were combined and washed with brine, and then dried over MgSO 4. The solvent was removed, using reduced pressure, and the residue was purified using column chromatography (0 to 10 percent ethyl acetate / dichloromethane), to give a red oil (10 milligrams). Example 56 The analytical data for the compounds described are summarized in the following table: 10 15 20 25 10 15 20 25 10 15 twenty 25 Example 57 Electrophysiology of Kv1.5 Autopatch Cells stably transfected with the cDNA for human Kv1.5 (in pEF6 :: VA-His-TOPO) were cultured in Dulbecco's modified Eagle's medium (DMEM) alpha-supplemented with serum fetal calf at 10 percent (FCS), 20 microliters / milliliter of penicillin (5,000 Units / milliliter), streptomycin (5,000 micrograms / milliliter), 10 microliters / milliliter [100x] glutamine, and blasticidin (7.5 micrograms / milliliter) . The external batch solution contained (in mM): NaCl 150, KCl 10, potassium gluconate 100, MgCl 2 3, CaCl 2 1, HEPES 10, pH 7.4. The patch pipettes were filled with an electrode solution of the composition of (in mM): KCl 160, MgCl20.5, HEPES 10, EGTA 1, pH 7.4 with KOH. The compounds were dissolved in dimethyl sulfoxide (100 percent), and filled into the external bath at a concentration of 1 μM. All experiments were conducted at room temperature (22-24 ° C). A cell suspension (10 milliliters), with a density of 100,000 cells / milliliter, was aliquoted into a 15 milliliter centrifuge tube, and transferred to an incubator (37 ° C, 5 percent CO2) for approximately 1 hour before to be used. Following the 60 minute incubation, a tube was taken and centrifuged at 1,000 revolutions per minute for 4 minutes at room temperature. Then 9.5 milliliters of the supernatant was discarded, leaving a cell granule at the bottom of the tube. Then the pellet was resuspended using 100 microliters of 0.2 percent bovine serum albumin solution / cold bath (4 ° C), filtered (0.22 microns) (0.02 grams of bovine serum albumin / 10 milliliters of bath). The bottom of the tube was gently shaken manually until the solution became cloudy with the cells. Then 100 microliters of cell resuspension solution was stored in the bank at 4 ° C (using a Peltier-based temperature control device) until used. A section of capillary glass (1B150F-4, WPI) was immersed in the solution of the cell suspension, so that approximately 3 centimeters of the fluid column were absorbed by the capillary action. An Ag / AgCl wire was dropped at the non-submerged end of the capillary as well. The exterior of the filled end with the capillary solution was then dried, and the capillary was loaded into the AutoPatch ™. Pipettes from the borosilicate glass patch (from a thin-walled filament GC150-TF capillary glass, with an OD of 1.5 millimeters, Harvard) were pulled using a DMZ pipette squeeze (Zeitz Instruments), and retro-filled using the solution of the internal pipette, taking care that no bubbles remain in the tip or in the body of the pipette. Patch pipettes typically had resistances of 2.3 to 3.5 mO. Once filled, the tip of the pipette and a proportion of the rod (approximately 1.5 m illimeters) were added in S igm acote (S igm a). Then the registration pipette was loaded in the A utoPatch R. The automated patch was started by the operator, but afterwards the AutoPatch.exe continued the experiment, providing that the previously established conditions and criteria were met.

The whole cell patch attachment records were made using the AutoPatch R rig, which incorporated an E PC9 amplifier (H EKA, Germany) under the control of the Pulse software (version 8.54, H EKA, Germany), a motion controller with two translators (Newport, United Kingdom), a valve controller (VF 1), and a c-level suction device, all at room temperature (22-24 ° C). This equipment was completely under the control of AutoPatch.exe, and there was only intervention by the operator when a requirement to fill in the drug deposits was presented, or to prevent the loss of a cell due to a technical error. Cells with an Rserie greater than 1 8MO were discounted from the experiment. The qualification stages before the perfusion and the application of the drug ensured that the observed current satisfied the criteria for the experiment. Only the cells with an I were used for the experiments. > 500 pA. The cells were continuously perfused with the external solution at a flow rate of 1.8 to 2 milli liters / minute. The perfusion chamber had a working volume of 80 to 85 microliters, and allowed a rapid exchange of the drug solutions. The on-line analysis of the hKv1.5 current during the application of the compounds was carried out by the AutoPatchM R software. Electrophysiology voltage step protocols and data analysis were carried out as follows . The data was sampled at 5 kHz, and filtered with a bandwidth of -3 d B of 2.5 kHz. The cells were maintained at a voltage of -80mV. Currents were caused up to one voltage step for 1, 000 millisecond of duration at OmV every 5 seconds. The currents were analyzed using the Pulsefit software (version 8.54, H EKA, Germany), the total load being measured during the entire voltage step. All other graphs were produced using the Igor Pro (WaveMetrics). The following table gives the electrophysiology data of Kv1 channel .5 for the representative compounds described therein. 10 15 20 25 Abbreviations Kv (ur) Rectifier delayed ultra-fast cardiac. CHO Chinese hamster ovary cells. DM EM Eagle Medium modified by Dulbecco. FCS Fetal calf serum. EBSS Earl balanced salt solution. WCPC Fastening of whole cell patch. References Herbert, "General principles of the structure of channels", Am. J. Med, 1 04, 87-98, 1 998. Armstrong and Hille, "Voltage-gated on channels and electrical excitability", Neuron , 20, 371-380, 1998. Gutman GA, Chandy KG, Adelman JP, Aiyar J, Bayliss DA, Clapham D. E., Covarriubias M, Desir G. V., Furuichi K., Ganetzky B, Garcia M. L., Grissmer S, Jan L. Y., Karschin A., Kim D., Kuperschmidt S., Kurachi Y., Lazdunski M., Lesage F., Lester H. A., McKinnon D., Nichols C. G., O'Kelly I., Robbins J., Robertson G. A., Rudy B., Sanguinetti M., Seino S., Stuehmer W., Tamkun M. M., Vandenberg C.A., Wei A, Wulff H., Wymore RS International Union of Pharmacology. XLI. Compendium of voltage-gated on channels: potassium channels. Pharmacol Rev., December 2003; 55 (4): 583-6. Shieh et al., "Potassium channels: molecular defects, diseases, and therapeutic opportunities", Pharmacol Rev, 52 (4), 557-594, 2000. Ford et al., "Potassium Channels: Gene Familia, Therapeutic Relevance, High-Throughput Screening Technologies and Drug Discovery ", Prog Drug Res, 58, 133-168, 2002. Marban" Cardiac channelopalthies ", Nature, 415, 213-218, 213-218, 2002. Brendel and Peukert" Blockers of the Kv1.5 Channel for the Treatment of Atrial Arrhythmias ", Expert Opinion in Therapeutic Patents, 12 (11), 1589-1598 (2002). Wang et al., "Sustained depolarization-induced outward current in human atrial myocytes." Evidence for a novel delayed rectifier K + current similar to Kv1.5 cloned channel currents ", Circ Res, 73, 1061-1076, 1993. Fedida et al., "Identity of a novel delayed rectifier from human heart with a cloned K + channel current", Circ Res, 73, 210-216, 1993. Feng et al. "Antisense oligodeoxynucleotides directed against Kv1.5 mRNA specifically inhibit ultrarapid delayed rectifier K + current in cultured adult human atrial myocytes", Circ Res, 80, 572-579, 1997. Amos and collaborators, "Differences between outward currents of human atrial and subepicardial ventricular myocytes ", J Physiol, 491, 31-50, 1996. Li et al," Evidence for two components of delayed rectifier K + current in human ventricular myocytes ", Circ Res, 78, 689-696, 1996. Nattel," Therapeutic implications of atrial fibrillation mechanisms: can mechanistic insights be used to improve AF management? " Cardiovascular Research, Volume 54, Edition 2, 347-360, 2002. Courtemanche et al., "Lonic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model", Cardiovasc Res, 42 (2), 477- 489, 1999. Nattel et al., "Cardiac ultrarapid delayed rectifiers: a novel potassium current family of functional similarity and molecular diversity", Cell Physiol Biochem, 9 (4-5), 217-226, 1999. Knobloch K., Brendel J ., Peukert S., Rosenstein B., Busch A.

E., Wirth K. J. Electrophysiological and antiarrhythmic effects of the novel l (Kur) channel blockers, S9947 and S20951, on left vs.. right pig atrium in vivo in comparison with the (Kr) blockers dofetilide, azimilide, d, l-sotalol and ibutilide. Naunyn Schmiedebergs Arch. Pharmacol., November 2002; 366 (5): 482-7. Wirth K. J., Paehler T, Rosenstein B., Knobloch K., Maier T., Frenzel J., Brendel J., Busch A.E., Bleich M. Atrial effects of the novel K (+) - channel-blocker AVE0118 in anesthetized pigs.

Cardiovasc Res., Nov 1; 60 (2): 298-306, 2003. Colatsky et al., "Channel specificity in antiarrhythmic drug action, Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias", Circulation, 82 (6), 1990. Feng et al., "Effects of class III antiarrhythmic drugs on transient outward and ultra-rapid delayed rectifier currents in human atrial myocytes", J. Pharmacol Exp. Ther., 281 (1), 384-392, 1997. Wang et al., "Effects of flecainide, quinidine, and 4-aminopyridine on transient outward and ultrarapid delayed rectifier currents in human atrial myocytes", J. Pharmacol, 272 (1), 184-196, nineteen ninety five. Malayev et al., "Mechanism of clofilium block of the human Kv1.5 delayed rectifier potassium channel", Mol Pharmaco, 147 (1), 198-205, 1995. Godreau et al., "Mechanisms of action of antiarrhythmic agent bertosamil on hKv1.5 channels and outward potassium current in human atrial myocytes", J. Pharmacol Exp. Ther.300 (2), 612-620, 2002. Matsuda et al., "Inhibition by a novel anti-arrhythmic agent, NIP-142, of cloned human cardiac K + channel Kv1.5 current", Life Sci, 68, 2017-2024, 2001. Bachmann and collaborators, "Characterization of a novel Kv1.5 channel blocker in Xenopus oocytes, CHO cells, human and rat cardiomyocytes", Naunyn Schmiedebergs Arch. Pharmacol, 364 (5), 472-478, 2001. Peukert S., Brendel J., Pirard B., Bruggemann A., Below P., Kleemann HW, Hemmerle H., Schmidt W. Identification, synthesis, and activity of novel blockers of the voltage-gated potassium channel Kv1.5. J. Med. Chem. Feb. 13; 46 (4): 486-98, 2003. Xu and Xu, "The expression of arrhythmic related genes on Xenopus oocytes for evaluation of class III antiarrhythmic drugs from ocean active material, "Yi Chuan Xue Bao, 27 (3), 195-201, 2000. Antonov et al., Synthesis of heterocyclic compounds based on adducts of polyhaloalkanes with unsaturated systems. Transformations of the trichloroethyl group in 2-methyl-3- (2,2,2-trichloroethyl) -4- (R-amino) furo [2,3-d] pyrimidines, their isomers and some of their precursors Khimiya Geterotsiklicheskikh Soedinenii (1994), (4), 450-6, Belenkii et al, Synthesis of heterocycles based on products of polyhaloalkanes to unsaturated systems.

Synthesis of substituted furo [2,3-d] pyrimidines. Khimiya Geterotsiklicheskikh Soedinenii (1993), (1), 124-9.

Claims (13)

1. CLAIMING IS 1 . A compound of Formula (I): wherein: R 1 is aryl, heteroaryl, cycloalkyl, or alkyl; R2 is H, alkyl, nitro, -CO2R7, CONR4R5, or halogen; R 3 is H, N R 4 R 5, NC (O) R 8, halogen, trifluoromethyl, alkyl, nitrile, or alkoxy; R4 and R5 may be the same or different, and may be H, alkyl, aryl, heteroaryl, or cycloalkyl; or R4 and R5 may together form a saturated, unsaturated, or partially saturated 4- to 7-membered ring, wherein this ring may optionally comprise one or more additional heteroatoms selected from N, O, or S; X is O, S, or N R6; R6 is H or alkyl; R7 is hydrogen, methyl, or ethyl; R8 is methyl or ethyl; L is (CH2) n, where n is 1, 2, or 3; and Y is aryl, a heterocyclic group, alkyl, alkenyl, or cycloalkyl; or pharmaceutically acceptable salts thereof. 2. A compound as claimed in claim 1, wherein R1 is aryl or heteroaryl, R2 is H or alkyl, R3 is H, NR4R5, alkoxy, or alkyl; X is O or NR6, R6 is H, n is 1 or 2, and Y is alkyl, cycloalkyl, aryl, or heteroaryl. 3. A compound as claimed in claim 2, wherein R1 is aryl or heteroaryl, R2 is H or methyl, R3 is H, NR4R5, alkoxy, or alkyl; X is NR6, R6 is H, n is 1, and Y is aryl or heteroaryl. 4. A compound as claimed in any of claims 1 to 3, wherein Y is phenyl, furanyl, thienyl, or pyridyl. 5. A compound as claimed in any one of claims 1 to 4, wherein Y is optionally substituted phenyl, optionally substituted furan-2-yl, or optionally substituted pyridin-2-yl. 6. A compound as claimed in claim 1, which is: 5-phenyl-N- (pyridin-2'-yl-methyl) -furo- [2,3-d] pyrimidin-4-amine, 5- (4-chloro-phenyl) -N- (pyridin-2'-yl-methyl) -furo- [2,3-d] -pyrimidin-4-amine, 6-methyl-5-phenyl-N- (pyridine- 2'-yl-methyl) -furo- [2,3-d] -pyrimidin-4-amine, (2-morpholin-4-yl-5-phenyl-furo- [2,3-d] -pyrimidin-4 -yl) -pyridin-2-yl-methyl-amine; 2 - ((2-hydroxy-ethyl) -. {5-phenyl-4 - [(pyridin-2-yl-methyl) -amino] -furo- [2,3-d] -pyrimidin-2-yl} -amino) -ethanol, 2 - ((2-hydroxy-ethyl) -. {5- (4-fluoro-phenyl) -4 - [(pyridin-2-yl-methyl) -amino] -furo- [2,3-d] -pyrimidin-2-yl.}. -amino) -ethanol, N 2 - (2-methoxy-ethyl) -5-phenyl-N 4 -pyridin-2-yl-methyl-furo- [2 , 3-d] -pyrim id in -2, 4-d amine, 2-. { 5-phenyl-4 - [(pyridin-2-yl-1-methyl-1-yl) -amino] -furo- [2, 3-d] -pyrimidin-2-yl-amino} -propan-1,3-diol, N2, N -dimethyl-5-phenyl-N -pyridin-2-yl-methyl-furo- [2,3-d] -pyrimidine-2,4-diamine, N, N -dimethyl-N- (6-methyl-pyridin-2-yl-methyl) -5-phenyl-furo- [2,3-d] -pyrimidin-2,4-diamine, or [2- (2-methoxy) ethoxy) -5-phenyl-furo- [2,3-d] -pyrimidin-4-yl] -pyridin-2-yl-methyl-amine. A process for the preparation of a compound as claimed in any of claims 1 to 6, which comprises: (i) reacting a compound of the Formula II with a suitable nucleophile XLY, optionally in the presence of a solvent and a base, and optionally at elevated temperature or with microwave irradiation; or (I) reacting a compound of Formula VI by displacing the substituent of 2-m ethan-its lfonyl with a suitable nucleophilic species; or (iii) reacting a compound of Formula X by displacing the 4-chloro substituent with a suitable nucleophilic species; 8. A pharmaceutical composition, which comprises at least one compound as claimed in any of claims 1 to 6, and optionally one or more excipients, diluents, and / or carriers. 9. A compound as claimed in any of claims 1 to 6, or a pharmaceutical composition comprising this compound, for use in medicine. A method for the treatment or prevention of a disorder requiring the inhibition of the potassium channel, which comprises administering to a subject, an effective amount of at least one compound as claimed in any of claims 1 to 6 , or a pharmaceutical composition as claimed in claim 8. 11. A method as claimed in claim 10, wherein said disorder is arrhythmia. 12. The use of a compound as defined in any of claims 1 to 6, in the manufacture of a medicament for use in the inhibition of the potassium channel. 13. The use as claimed in claim 12, wherein the medicament is for use in the treatment or prevention of arrhythmia. RESU MEN A compound of Formula (I): wherein R 1 is aryl, heteroaryl, cycloalkyl, or alkyl; R2 is H, alkyl, nitro, -CO2R7, CONR4R5, or halogen; R 3 is H, N R 4 R 5, NC (O) R 8, halogen, trifluoromethyl, alkyl, nitrile, or alkoxy; R4 and R5 may be the same or different, and may be H, alkyl, aryl, heteroaryl, or cycloalkyl; or R4 and R5 may together form a 4 to 7 saturated, unsaturated, or partially saturated ring, wherein this ring may optionally comprise one or more additional heteroatoms selected from N, O, or S; X is O, S, or N R6; R6 is H or alkyl; R7 is hydrogen, methyl, or ethyl; R8 is methyl or ethyl; L is (CH2) n, where n is 1, 2, or 3; and Y is aryl, a heterocyclic group, alkyl, alkenyl, or cycloalkyl; together with pharmaceutically acceptable salts thereof. The use of these compounds as inhibitors of the potassium channel is also described. * * * * *