# Patent

## Title
Furanopyrimidine compounds as potassium ion channel inhibitors

## 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;
        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 potassium channel inhibitors is also described.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 60/578,350, filed Jun. 10, 2004, the entirety of which is hereby incorporated by reference herein. This application claims priority under 35 U.S.C. § 119(a)-(d) to Great Britain Application No. GB 0412986.2, filed Jun. 10, 2004, the entirety of which is hereby incorporated by reference herein.


BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to furanopyrimidine compounds which are potassium channel inhibitors. Pharmaceutical compositions comprising the compounds and their use in the treatment of arrythmia are also provided.
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+, Ca2+ 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 al., 2003).
Compounds which 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, Kir2.1, HERG, KVLQT1/minK, and Kv1.5 are involved in the repolarisation phase of the action potential in cardiac atrial myocytes. These potassium channel subtypes have been associated with cardiovascular diseases and disorders including long QT syndrome, hypertrophy, ventricular fibrillation, and atrial fibrillation, all of which can cause cardiac failure and fatality (Marban, 2002).
The human delayed rectifier voltage gated potassium channel subunit, Kv1.5, is exclusively expressed in atrial myocytes and is believed to offer therapeutic opportunities for the management of atrial fibrillation for several different reasons (see review of Brendel and Peukert, 2002): (i) There is evidence that Kv1.5 underlies the cardiac ultrarapid delayed rectifier (Kv(ur)) physiological current in humans due to similar biophysical and pharmacological properties (Wang et al., 1993; and Fedida et al., 1993). This has been supported with antisense oligonucleotides to Kv1.5 which have been shown to reduce Kv(ur) amplitude in human atrial myocytes (Feng et al., 1997). (ii) electrophysiological recordings have demonstrated that Kv(ur) is selectively expressed in atrial myocytes, and therefore avoids inducing potentially fatal ventricular arrhythmia through interfering with ventricular repolarisation (Amos et al., 1996; Li et al., 1996; and Nattel, 2002). (iii) Inhibiting Kv(ur) in atrial fibrillation-type human atrial myocytes prolonged the action potential duration compared to normal healthy human atrial myocytes (Courtemanche et al., 1999). (iv) Prolonging the action potential duration by selectively inhibiting Kv1.5 could present safer pharmacological interventions for protecting against atrial re-entrant arrhythmias such as atrial fibrillation and atrial flutter compared to traditional class III antiarrythmics, by prolonging the atrial refractory period while leaving ventricular refractoriness unaltered (Nattel et al., 1999, Knobloch et al., 2002; and Wirth et al., 2003). Class III antiarrythmics have been widely reported as a preferred method for treating cardiac arrhythmias (Colatsky et al., 1990).
Traditional and novel class III antiarrythmic potassium channel blockers have been reported to have a mechanism of action by directly modulating Kv1.5 or Kv(ur). The known class III antiarrythmics ambasilide (Feng et al., 1997), quinidine (Wang et al., 1995), clofilium (Malayev et al., 1995) and bertosamil (Godreau et al., 2002) have all been reported as potassium channel blockers of Kv(ur) in human atrial myocytes. The novel benzopyran derivative, NIP-142, blocks Kv1.5 channels, prolongs the atrial refractory period and terminates atrial fibrillation and flutter in in vivo canine models (Matsuda et al., 2001), and S9947 inhibited Kv1.5 stably expressed in both Xenopus oocytes and Chinese hamster ovary (CHO) cells and KV(ur) in native rat and human cardiac myocytes (Bachmann et al., 2001). Elsewhere, other novel potassium channel modulators which target Kv1.5 or Kv(ur) have been described for the treatment of cardiac arrhythmias, these include biphenyls (Peukert et al 2003), thiophene carboxylic acid amides (WO0248131), bisaryl derivatives (WO0244137, WO0246162), carbonamide derivatives (WO0100573, WO0125189), anthranillic acid amides (WO2002100825, WO02088073, WO02087568), dihydropyrimidines (WO0140231), cycloakyl derivatives (WO03063797), indane derivatives (WO0146155, WO9804521), tetralin benzocycloheptane derivatives (WO9937607), thiazolidone and metathiazanone derivatives (WO9962891), benzamide derivatives (WO0025774), isoquinoline derivatives (WO0224655), pyridazinone derivatives (WO9818475, WO9818476), chroman derivatives (WO9804542), benzopyran derivatives (WO0121610, WO03000675, WO0121609, WO0125224, WO02064581), benzoxazine derivatives (WO0012492), and the novel compound A1998 purified from Ocean material (Xu & Xu, 2000).
Several further publications disclose compounds which are indicated as acting on potassium channels. Thus, U.S. Pat. No. 6,531,495 discloses 2′-aminomethylbiphenyl-2-carboxamides, WO2002/100825 discloses anthranillic acid amides as antiarrhythmics and WO2002/036556 discloses acylaminoalkylbenzenesulfonamides as cardiovascular agents.
Furanopyrimidines have been reported to be useful as folate inhibitors, anti-histamines, muscle relaxants and agrochemicals. Furanopyrimidines have not previously been reported as useful agents for modulating ion channels.
The synthesis of various 4-amino substituted furanopyrimidines has been reported (Antonov et al., 1994) as well as certain 4-benzylamino substituted furanopyrimidines (Belenkii et al., 1993).
Furanopyrimidines substituted in the 5-position with an alkyl group have been identified as pesticides and fungicides. Thus EP459611 discloses a family of 4-phenylethyl derivatives, whilst EP196524 discloses a series of 4-phenoxypropyl derivatives.
Furanopyrimidines substituted with an alkyl group at the 5-position have also been disclosed as having muscle-relaxant activity (JP48081893 and DE1817146).
BRIEF SUMMARY OF THE INVENTION
This invention provides compounds that are potassium channel inhibitors. Specifically, furanopyrimidines with an aromatic or heteroaromatic substituent at the 5-position are disclosed. These compounds are particularly useful for inhibiting potassium channels Kv1.5 or Kv(ur), which are known targets for the treatment of cardiac arrhythmia in the atria such as atrial fibrillation (Nattel et al., 1999; Wang et al., 1993). This invention is not limited to treating cardiac arrythmias, the compounds also being useful to treat other diseases which require potassium channel inhibition (e.g., Shieh et al., 2000; Ford et al., 2002).


DETAILED DESCRIPTION OF THE INVENTION
Thus, in a first aspect, the present invention provides 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, NR6C(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;
        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 from 1 to 6 carbon atoms, such as a C1-C4 alkyl group or moiety, for example methyl, ethyl, n-propyl, i-propyl, butyl, i-butyl and t-butyl. An alkyl group or moiety may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries one or two substituents. Suitable substituents include halogen, cyano, nitro, NR9R10, alkoxy, hydroxyl, unsubstituted aryl, unsubstituted heteroaryl, CO2R7, C(O)NR9R10, NR6C(O)R8 and SO2NR9R10.
As used herein, an aryl group is typically a C6-C10 aryl group such as phenyl or napthyl. 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, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, NR9R10, CO2R7, C(O)NR9R10, NR6C(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 pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl and pyrazolyl groups. Preferred heteroaryl groups are furanyl, thienyl and pyridyl. Examples of polycyclic heterocycles include indolyl, benzofuranyl, benzothiophenyl and benzodioxolyl. Non-aryl heterocyclic groups are also included, such as tetrahydrofuranyl or pyrrolidinyl. A heterocyclic group may be unsubstituted or substituted at any position. Suitable substituents include cyano, nitro, halogen, alkyl, alkylthio, alkoxy, NR9R10, CO2R7, C(O)NR9R10, NR6C(O)R8 and SO2NR9R10 and hydroxyl.
R9 and R10 can be the same or different, and may be selected from H, unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl, aminoethyl, methylaminoethyl, dimethylaminoethyl, hydroxyethyl, alkoxyethyl, or R9 and R10 may together form a saturated, unsaturated or partially saturated 4 to 7 member ring.
When R4 and R5 or R9 and R10 together form a saturated, unsaturated or partially saturated 4 to 7 member ring, the ring may optionally comprise one, two, or three further heteroatoms.
As used herein, alkoxy means C1-3 alkoxy, cycloalkyl means C3-6 cycloalkyl and halogen means Cl, F, Br, or I, preferably Cl, F or Br.
Preferred compounds of formula I are those 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.
More preferred compounds of formula I are those 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.
Preferably Y is phenyl, furanyl, thienyl or pyridyl. More preferably Y is optionally substituted phenyl, furan-2-yl or pyridine-2-yl.
Preferred compounds include:
5-Phenyl-N-(pyridin-2′-ylmethyl)furo[2,3-d]pyrimidin-4-amine,
5-(4-Chlorophenyl)-N-(pyridin-2′-ylmethyl)furo[2,3-d]pyrimidin-4-amine,
6-Methyl-5-phenyl-N-(pyridin-2′-ylmethyl)furo[2,3-d]pyrimidin-4-amine,
(2-Morpholin-4-yl-5-phenyl-furo[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine,
2-((2-Hydroxyethyl)-{5-Phenyl-4-[(pyridine-2-ylmethyl)-amino]-furo[2,3-d]pyrimidin-2-yl}-amino)-ethanol,

    
    
        2-((2-Hydroxyethyl)-{5-(4-Fluoro-phenyl)-4-[(pyridine-2-ylmethyl)-amino]-furo[2,3-d]pyrimidin-2-yl}-amino)-ethanol,
    
    


N2-(2-Methoxyethyl)-5-phenyl-N4-pyridin-2-ylmethyl-furo[2,3-d]pyrimidine-2,4-diamine,
2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]furo[2,3-d]pyrimidin-2-ylamino}-propane-1,3-diol,
N2,N2-Dimethyl-5-phenyl-N4-pyridin-2-ylmethyl-furo[2,3-d]pyrimidine-2,4-diamine,
N2,N2-Dimethyl-N4-(6-methyl-pyridin-2-ylmethyl)-5-phenyl-furo[2,3-d]pyrimidine-2,4-diamine, or
[2-(2-Methoxyethoxy)-5-phenyl-furo[2,3-d]pyrimidin-4-yl]-pyridin-2ylmethylamine,
and pharmaceutically acceptable salts thereof.
Compounds of formula I wherein R3═H are conveniently synthesised from a compound of formula II by reaction with a suitable nucleophile HX-L-Y (where 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. Optionally the reaction may be carried out in a microwave reactor.




A compound of formula II may be obtained from a compound of formula III by reaction with a trialkyl orthoformate in a suitable solvent or no solvent, and with heating. Preferably the trialkyl orthoformate is triethyl orthoformate. Preferably a solvent is present. Suitable solvents include acetic anhydride. When a solvent is present the reaction is carried out at reflux temperature.




Compounds of formula III may be obtained by the reaction of a compound of formula IV with malononitrile. The reaction may 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. Preferably a base is present. Suitable bases include hindered organic amines such as triethylamine.




A compound of formula IV can be prepared by reaction of a compound of formula V under oxidative conditions. Preferred oxidizing agents include [bis(trifluoroacetoxy) iodo] benzene. The reaction is preferably 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 reflux temperature.




In an alternative synthesis of 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 may 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 may be prepared by oxidation of a compound of formula VIII. Suitable conditions include the use of a peroxide reagent in an organic acid. Preferably the peroxide reagent is hydrogen peroxide and the organic acid is acetic acid.




A compound of formula VIII may be prepared by reaction of a compound of formula IX under alkylating conditions. Suitable conditions include the use of a methyl iodide, under basic conditions. Preferably the basic conditions comprise a metal hydroxide in a mixture of 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 may be conveniently prepared by reaction of a compound of formula III with potassium ethyl xanthate. Preferably the reaction is carried out in alcohol. Preferably the alcohol is butanol.
In a further method, particularly applicable to 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 a 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. Alternatively the reaction may be carried out with microwave heating.




A compound of formula X may be prepared by reaction of a compound of formula XI with a suitable chlorinating reagent. Preferably the chlorinating reagent is thionyl chloride, phosphorous oxychloride or diphenylphosphinic chloride. Preferably the reaction is carried out in the presence of a base such as an amine base. Preferred bases include triethylamine and diethylaniline. Optionally the base may also serve as the solvent. The reaction is carried out at 60-100° C.




Compounds of formula XI may be prepared by 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.




Compounds of formula XII are readily prepared from 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 at below 5° C.
It is understood that compounds of formula I wherein R3 is a carboethoxy group may undergo functional group transformation of the ester moiety using methods familiar to those skilled in the art. In a preferred instance such compounds may undergo amidation by reaction with an alkyl or dialkylamine. In another preferred instance compounds of formula I wherein R3 is a 1-hydroxyethyl group can be prepared by the reaction with a reducing agent such as diisobutylaluminium hydride or lithium aluminium hydride. In a further instance compounds of formula I wherein R3 is a carboethoxy group may be reacted with a dialkyl carbonate under basic conditions to provide a compound of formula I wherein R3 is a dialkylmalonyl group. Such compounds may be reduced, preferably with a reducing agent such as diisobutylaluminium hydride or lithium aluminium hydride, to provide compounds of formula I wherein R3 is a propanediol group.
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. Synthetic methods can also be found in reviews; thiophenes for example can be found in references cited in Comprehensive Heterocyclic Chemistry, Eds Katritzky, A. R., Rees, C. R., (4), 863-934, and Comprehensive Heterocyclic Chemistry (II), Eds Katritzky, A. R., Rees, C. W., Scriven, E. F. V., (2), 607-678.
Suitable starting materials include:















Material
Reference
Supplier









4′-Fluoroacetophenone
F-320-7
Aldrich



1-(4-Fluorophenyl)-propan-1-one
F-12,841-4
Aldrich



Acetophenone
A1 070-1
Aldrich



2-(Aminomethyl)pyridine
A6,520-4
Aldrich



2-Furfurylamine
F20009
Aldrich



4′-Chloroacetophenone
C1,970-8
Aldrich



1-(3,4-Dimethoxyphenyl)ethanone
15,663-9
Aldrich



1-(1,3-Benzodioxol-6-yl)ethanone
17,902-7
Aldrich



Propiophenone
P5,160-5
Aldrich



Malononitrile
12527-1000
Acros



Ethyl malonyl chloride
252-934-5
Lancaster










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 pharmaceutical formulation comprising at least one compound of the invention and optionally one or more excipients, carriers or diluents, wherein said compound has the formula:




Wherein
R1 is aryl, heteroaryl, cycloalkyl or alkyl;
R2 is H, alkyl, nitro, —CO2R7, CONR4R5 or halo;
R3 is H, NR4R5, NR6C(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;
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 dose forms containing a predetermined amount of each active ingredient per dose. Such a unit may be adapted to provide 5-100 mg/day of the compound, preferably either 5-15 mg/day, 10-30 mg/day, 25-50 mg/day 40-80 mg/day or 60-100 mg/day. For compounds of formula I, doses in the range 100-1000 mg/day are provided, preferably either 100-400 mg/day, 300-600 mg/day or 500-1000 mg/day. Such doses can be provided in a single dose or as a number of discrete doses. The ultimate dose will of course 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.
In a further aspect the present invention provides a compound, or a pharmaceutical composition comprising said compound for use in medicine, wherein said compound has the formula:




Wherein
R1 is aryl, heteroaryl, cycloalkyl or alkyl;
R2 is H, alkyl, nitro, CO2R7, CONR4R5 or halo;
R3 is H, NR4R5, NR6C(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;
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 which require inhibition of potassium channels, for example in the treatment of arrythmia. Thus, in further aspects, the present invention provides:
(i) a method of treating or preventing a disorder which requires potassium channel inhibition, eg arrythmia, comprising administering to a subject an effective amount of at least one compound or of a pharmaceutical composition comprising said at least one compound and optionally one or more excipients, diluents and/or carriers wherein said compound has the formula:




Wherein
R1 is aryl, heteroaryl, cycloalkyl or alkyl;
R2 is H, alkyl, nitro, CO2R7, CONR4R5 or halo;
R3 is H, NR4R5, NR6C(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;
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 potassium channel inhibition; wherein the compound has the formula:




Wherein
R1 is aryl, heteroaryl, cycloalkyl or alkyl;
R2 is H, alkyl, nitro, CO2R7, CONR4R5 or halo;
R3 is H, NR4R5, NR6C(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;
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.
In particular, the medicament is for use in the treatment or prevention of arrhythmia.
Preferably the compounds are compounds of the first aspect.
EXAMPLES
Using the information outlined herein the following compounds can be synthesised which are given by way of example only. The pharmacological profile of compounds of the present invention can readily be assessed by those skilled in the art using routine experimentation, such as procedures and techniques illustrated herein and described in detail in Ford et al., 2002.
Example 1
1-(4-Fluorophenyl)-2-hydroxyethanone
Under a nitrogen atmosphere, a stirred solution of 4′-fluoroacetophenone (1.15 g, 8.32 mmol) in acetonitrile (42 ml) was treated with [bis(trifluoroacetoxy)iodo]benzene (7.16 g, 16.6 mmol) followed by water (8.3 ml) and trifluoroacetic acid (1.3 ml). The resultant solution was heated under reflux for 2 hr before standing overnight at ambient temperature. The solvent was then removed in vacuo; water (30 ml) was added and the mixture extracted with dichloromethane (3×30 ml). The combined extracts were washed with saturated sodium hydrogen carbonate solution (30 ml) followed by brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo to give the crude 1-(4-fluorophenyl)-2-hydroxyethanone which was purified by flash chromatography (silica) eluting with ethyl acetate and 40°-60° C. petroleum ether (3:1) to give a white solid (0.55 g).
Examples 2 to 7
The compounds set out below were prepared in the same way as in Example 1, using the appropriate starting materials.











Example
Compound







2
2-Hydroxy-1-phenylethanone


3
1-(4-Chlorophenyl)-2-hydroxyethanone


4
1-(3,4-Dimethoxyphenyl)-2-hydroxyethanone


5
1-(1,3-Benzodioxol-5-yl)-2-hydroxyethanone


6
2-Hydroxy-1-phenylpropan-1-one


7
1-(4-Fluorophenyl)-2-hydroxypropan-1-one









Example 8
2-Amino-4-(4-fluorophenyl)-3-furonitrile
A solution of malononitrile (0.31 g, 4.65 mmol) and triethylamine (0.65 ml, 4.65 mmol) in methanol (5 ml) was added drop-wise to a stirred suspension of 2-hydroxy-4′-fluoroacetophenone (0.65 g, 4.22 mmol) in methanol (16 ml) under a nitrogen atmosphere at ambient temperature. When the addition was complete, the mixture was stirred for 18 hr at ambient temperature. The solvent was then removed in vacuo, water (50 ml) was then added to the residue and the mixture was extracted with dichloromethane (3×50 ml). The combined extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude 2-amino-4-(4′-fluorophenyl)-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′-fluoroacetophenone (0.60 g), which was used without further purification.
Examples 9 to 13
The compounds set out below were prepared in the same way as in Example 8, using the appropriate starting materials.











Example
Compound
















9
2-Amino-4-phenyl-3-furonitrile


10
2-Amino-4-(4′-chlorophenyl)-3-furonitrile


11
2-Amino-4-(3′,4′-dimethoxyphenyl)-3-



furonitrile


12
2-Amino-4-(1′,3′-benzodioxol-5-yl)-3-



furonitrile


13
2-Amino-5-methyl-4-phenyl-3-furonitrile


14
2-Amino-4-(4-fluorophenyl)-5-



methylthiophene-3-carbonitrile









Example 15
Ethyl 3-cyano-4-(4-fluorophenyl)-2-furylimidoformate
A stirred mixture of 2-amino-4-(4-fluorophenyl)-3-furonitrile (0.27 g, 1.36 mmol) and triethyl orthoformate (0.95 ml) was treated with acetic anhydride (0.65 ml) and then heated under reflux for 4 hr. The solvents were then removed in vacuo to give Ethyl 3-cyano-4-(4-fluorophenyl)-2-furylimidoformate as a brown solid (0.35 g), which was used without further purification.
Examples 16 to 20
The compounds set out below were prepared in the same way as in Example 15, using the appropriate starting materials.











Example
Compound







16
Ethyl 3-cyano-4-phenyl-2-



furylimidoformate


17
Ethyl 4-(4-chlorophenyl)-3-cyano-2-



furylimidoformate


18
Ethyl 3-cyano-4-(3,4-



dimethoxyphenyl)-2-



furylimidoformate


19
Ethyl 4-(1,3-benzodioxol-5-yl)-3-



cyano-2-furylimidoformate


20
Ethyl 3-cyano-5-methyl-4-phenyl-2-



furylimidoformate









Example 21
5-(4-Fluorophenyl)-N-(pyridin-2-ylmethyl)furo[2,3-d]pyrimidin-4-amine
A stirred reaction mixture of the crude ethyl 3-cyano-4-(4-fluorophenyl)-2-furylimidoformate (0.35 g, 1.36 mmol) and pyridin-2-yl-methylamine (0.16 ml, 1.50 mmol) in ethanol (3.5 ml) was heated under reflux for 4 hr. The resultant mixture was cooled to ambient 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-fluorophenyl)-N-(pyridin-2-ylmethyl)furo[2,3-d]pyrimidin-4-amine (0.15 g) as an off-white solid, m.pt. 162′-164° C.
Examples 22 to 26
The compounds set out below were prepared in the same way as in Example 21, using the appropriate starting materials.











Example
Compound







22
5-Phenyl-N-(pyridin-2′-ylmethyl)furo[2,3-



d]pyrimidin-4-amine


23
5-(4-Chlorophenyl)-N-(pyridin-2′-



ylmethyl)furo[2,3-d]pyrimidin-4-amine


24
5-(3,4-Dimethoxyphenyl)-N-(pyridin-2′-



ylmethyl)furo[2,3-d]pyrimidin-4-amine


25
5-(1,3-Benzodioxol-5′-yl)-N-(pyridin-2′-



ylmethyl)furo[2,3-d]pyrimidin-4-amine


26
6-Methyl-5-phenyl-N-(pyridin-2′-



ylmethyl)furo[2,3-d]pyrimidin-4-amine









Example 27
5-Phenyl-1H-furo[2,3-d]pyrimidine-2,4-dithione
A stirred mixture of 2-amino-4-phenyl-furan-3-carbonitrile (5.0 g, 0.027 mol) and potassium ethyl xanthate (4.5 g, 0.027 mol) in butan-1-ol (25 ml) was heated for 2 hr at 110° C. After cooling to ambient temperature, the solid was filtered off, washed with a little butan-1-ol and dissolved in water (100 ml). The solution was then acidified with glacial acetic acid to give a light-brown precipitate. This was filtered off, washed with water and dried in vacuo to give the crude 5-phenyl-1H-furo[2,3-d]pyrimidine-2,4-dithione (3.0 g) which was used without further purification.
Examples 28 to 29
The compounds set out below were prepared in the same way as in Example 27, using the appropriate starting materials.











Example
Compound







28
6-Methyl-5-phenyl-1H-furo[2,3-



d]pyrimidine-2,4-dithione


29
5-(4-Fluorophenyl)-6-methyl-1H-



furo[2,3-d]pyrimidine-2,4-dithione









Example 30
2,4-Bis-methylsulfanyl-5-phenyl-furo[2,3-d]pyrimidine
A stirred mixture of 5-phenyl-1H-furo[2,3-d]pyrimidine-2,4-dithione (3.0 g, 0.012 mol) in ethanol (100 ml) and potassium hydroxide (1.4 g, 0.024 mol) in water (25 ml) was treated with iodomethane (3.6 g, 1.6 ml, 0.025 mol). After 3 hr at ambient temperature, the mixture was diluted with water (250 ml) and extracted with dichloromethane (3×100 ml). The combined extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude 2,4-bis-methylsulfanyl-5-phenyl-furo[2,3-d]pyrimidine which was purified by flash chromatography (silica) eluting with dichloromethane to give a brown solid (3.0 g).
Examples 31 to 32
The compounds set out below were prepared in the same way as in Example 30, using the appropriate starting materials.











Example
Compound







31
2,4-Bis-methylsulfanyl-6-



methyl-5-phenyl-1H-furo[2,3-



d]pyrimidine


32
2,4-Bis-methylsulfanyl-5-(4-



fluorophenyl)-6-methyl-1H-



furo[2,3-d]pyrimidine









Example 33
2,4-Bis-methylsulfonyl-5-phenyl-furo[2,3-d]pyrimidine
A stirred suspension of 2,4-bis-methylsulfanyl-5-phenyl-furo[2,3-d]pyrimidine (1.5 g, 5.21 mmol) in glacial acetic acid (15 ml) was treated with hydrogen peroxide (3.6 ml of a 27.5% aqueous solution, 33.3 mmol). After 2 hr at ambient temperature, the mixture was heated to obtain an homogenous solution and then stirred at ambient temperature for 18 hr. The reaction mixture was then diluted with water (50 ml) and extracted with dichloromethane (3×50 ml). The combined extracts were washed with an aqueous solution of sodium metabisulfite (2×50 ml) followed by saturated aqueous sodium hydrogen carbonate (50 ml) before being dried (MgSO4). The solvent was removed in vacuo to give the crude 2,4-bis-methylsulfonyl-5-phenyl-furo[2,3-d]pyrimidine which was purified by flash chromatography (silica) eluting with ethyl acetate to give a white solid (0.5 g).
Examples 34 to 35
The compounds set out below were prepared in the same way as in Example 33, using the appropriate starting materials.











Example
Compound







34
2,4-Bis-methylsulfonyl-6-methyl-



5-phenyl-1H-furo[2,3-



d]pyrimidine


35
2,4-Bis-methylsulfonyl-5-(4-



fluorophenyl)-6-methyl-1H-



furo[2,3-d]pyrimidine









Example 36
(2-Methanesulfonyl-5-phenyl-furo[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethylamine
A mixture of 2,4-bis-methylsulfonyl-5-phenyl-furo[2,3-d]pyrimidine (54 mg, 0.153 mmol), triethylamine (17 mg, 0.168 mmol) and 2-(aminomethyl)pyridine (18 mg, 0.168 mmol) in propan-2-ol (5 ml) was warmed to obtain a solution and stirred at ambient temperature for 2.5 hr. Water (50 ml) was then added and the mixture was extracted with dichloromethane (3×30 ml). The combined extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude (2-methanesulfonyl-5-phenyl-furo[2,3d]pyrimidin-4-yl)-pyridin-2-ylmethylamine which was purified by flash chromatography (silica) eluting with 40′-60° C. petroleum ether followed by ethyl acetate to give a white solid (17 mg), m.pt. 171-173° C.
Examples 37 to 40
The compounds set out below were prepared in the same way as in Example 36, using the appropriate starting materials.











Example
Compound







37
(2-Methanesulfonyl-5-phenyl-furo[2,3-



d]pyrimidin-4-yl)-(6-methylpyridin-2-



ylmethyl)-amine


38
Furan-2-ylmethyl-(2-methanesulfonyl-5-



phenyl-furo[2,3-d]pyrimidin-4-yl)-amine


39
(2-Methanesulfonyl-6-methyl-5-phenyl-



furo[2,3-d]pyrimidin-4-yl)-pyridin-2-



ylmethylamine


40
[5-(4-Fluorophenyl)-2-methanesulfonyl-



6-methyl-furo[2,3-d]pyrimidin-4-yl]-



pyridin-2-ylmethylamine









Example 41
N2-(2-Methoxyethyl-N4-pyridin-2-ylmethyl-furo[2,3-d]pyrimidine-2,4-diamine
A stirred mixture of (2-methanesulfonyl-5-phenyl-furo[2,3d]pyrimidin-4-yl)-pyridin-2-ylmethylamine (50 mg, 0.132 mmol), triethylamine (15 mg, 0.145 mmol) and 2-methoxyethylamine (10 mg, 0.197 mmol) in ethanol (1 ml) was heated by microwave irradiation at 180° C. for 30 mins. The resultant solution was diluted with water (30 ml) and extracted with dichloromethane (3×30 ml). The combined extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude N2-(2-methoxyethyl)-5-phenyl-N4-pyridin-2-ylmethyl-furo[2,3-d]pyrimidine-2,4-diamine which was purified by flash chromatography (silica) eluting with dichloromethane followed by ethyl acetate and dichloromethane (2:1) to give an off-white solid (26 mg), m.pt. 96-98° C.
Examples 42 to 45
The compounds set out below were prepared in the same way as in Example, 41 using the appropriate starting materials.











Example
Compound







42
(2-Morpholin-4-yl-5-phenyl-



furo[2,3-d]pyrimidin-4-yl)-puridin-



2-ylmethyl-amine


43
2-((2-Hydroxyethyl)-{5-Phenyl-4-



[(pyridine-2-ylmethyl)-amino]-



furo[2,3-d]pyrimidin-2-yl}-amino)-



ethanol


44
2-{5-Phenyl-4-[(pyridin-2-



ylmethyl)-amino]furo[2,3-



d]pyrimidin-2-ylamino}-propane-



1,3-diol


45
2-((2-Hydroxyethyl)-{5-(4-



fluorophenyl)-4-[(pyridine-2-



ylmethyl)-amino]-furo[2,3-



d]pyrimidin-2-yl}-amino)-ethanol









Example 46
N2,N2-Dimethyl-5-phenyl-N4-pyridin-2-ylmethyl-furo[2,3-d]pyrimidine-2,4-diamine
Ethanol (1 ml) was saturated with dimethylamine and (2-methanesulfonyl-5-phenyl-furo[2,3d]pyrimidin-4-yl)-pyridin-2-ylmethylamine (50 mg, 0.132 mmol) was added. The mixture was then stirred and heated by microwave irradiation at a pressure of 250 psi for 30 mins, the temperature reaching a maximum of 138° C. The resultant solution was then diluted with water (50 ml) and extracted with dichloromethane (3×50 ml). The combined extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude N2,N2-dimethyl-5-phenyl-N4-pyridin-2-yl methyl-furo[2,3-d]pyrimidine-2,4-diamine which was purified by flash chromatography (silica) eluting with dichloromethane followed by dichloromethane and ethyl acetate (9:1) to give an off-white solid (19 mg), m.pt. 108-110° C.
Examples 47 to 50
The compounds set out below were prepared in the same way as in Example 45, using the appropriate starting materials.











Example
Compound







47
N2,N2-Dimethyl-N4-(6-methyl-pyridin-2-



ylmethyl)-5-phenyl-furo[2,3-



d]pyrimidine-2,4-diamine


48
N4-Furan-2-ylmethyl-N2,N2-dimethyl-5-



phenyl-furo[2,3-d]pyrimidine-2,4-



diamine


49
6,N2,N2-Trimethyl-5-phenyl-N4-pyridin-



2-ylmethyl-furo[2,3-d]pyrimidine-2,4-



diamine


50
5-(4-Fluorophenyl)-6,N2,N2-trimethyl-



N4-pyridin-2-ylmethyl-furo[2,3-



d]pyrimidine-2,4-diamine









Example 51
[2-(2-Methoxyethoxy)-5-phenyl-furo[2,3-d]pyrimidin-4-yl]-pyridin-2-ylmethylamine
Stirred 2-methoxyethanol (1 ml) was treated with 60% sodium hydride (10 mg) followed, after 10 mins, by (2-methanesulfonyl-5-phenyl-furo[2,3d]pyrimidin-4-yl)-pyridin-2-ylmethylamine (50 mg, 0.132 mmol) and heated by microwave irradiation for 30 mins at 150° C. The resultant solution was then diluted with water (50 ml) and extracted with dichloromethane (3×50 ml). The combined extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude [2-(2-methoxyethoxy)-5-phenyl-furo[2,3-d]pyrimidin-4-yl]-pyridin-2-ylmethylamine which was purified by flash chromatography (silica) eluting with 40′-60° C. petroleum ether followed by 40′-60° C. petroleum ether and ethyl acetate (1:1) to give an off-white solid (30 mg), m.pt. 97-99° C.
Example 52
Ethyl 3-[(3-cyano-4-phenyl-2-furyl) amino]-3-oxopropanoate
Ethyl malonyl chloride (3.8 ml, 29.89 mmol) was added dropwise to a solution of 2-amino-4-phenyl-3-furonitrile (5 g, 27.17 mmol) and triethylamine (4.2 ml, 29.89 mmol) in THF (30 ml) maintaining temperature below 5° C. under nitrogen. This was allowed to warm up to room temperature and stirred for 2 hr. The reaction mixture was diluted with water and extracted with DCM. The organic layers were combined and washed with brine and dried over MgSO4. The solution was filtered and solvent removed under reduced pressure. The residue was purified by column chromatography using DCM isolating an orange oil (3.7 g, 46%).
Example 53
Ethyl (4-oxo-5-phenyl-3,4-dihydrofuro[2,3-d]pyrimin-2-yl)acetate
3-[(3-Cyano-4-phenyl-2-furyl)amino]-3-oxopropanoate (1.2 g, 4.2 mmol) was added to a solution of 4M hydrogen chloride in dioxane (20 ml) and heated to reflux with stirring for 2 hr. The reaction mixture was cooled to room temperature and poured into saturated sodium hydrogen carbonate solution. The aqueous phase was extracted with DCM. 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 DCM to provide a brown solid (0.925 g).
Example 54
Ethyl (4-chloro-5-phenylfuro[2,3-d]pyrimin-2-yl)acetate
Ethyl (4-oxo-5-phenyl-3,4-dihydrofuro[2,3-d]pyrimin-2-yl)acetate (827 mg, 2.79 mmol) was added to a solution of phosphorus oxychloride (13 ml, 139.5 mmol) and diethyl aniline (4.4 ml, 27.8 mmol) and heated to 65C and stirred for 2.5 hr. Phosphorous oxychloride was removed under reduced pressure and the residue was diluted with DCM. The organic layer was washed with water twice and then with saturated sodium hydrogen carbonate solution and finally with brine. The solution was dried over MgSO4 and filtered. Solvent was removed under reduced pressure and the residue was purified by column chromatography (20-100% DCM/40′-60′ petrol) to provide an orange oil (100 mg).
Example 55
Ethyl {5-phenyl-4-[(pyridine-2-ylmethyl)amino]furo[2,3-d]pyrimidin-2-yl}-acetate
2-Aminomethyl pyridine (36 microL, 0.347 mmol) was added to a solution of ethyl (4-chloro-5-phenylfuro[2,3-d]pyrimin-2-yl)acetate (100 mg, 0.316 mmol) and triethylamine (48 microL, 0.347 mmol) in ethanol (5 ml) and heated to reflux for 4 hr. The reaction mixture was cooled and diluted with water. The aqueous mixture was extracted three times with DCM. The organic phases were combined and washed with brine then dried over MgSO4. The solvent was removed using reduced pressure and the residue was purified using column chromatography (0-10% ethyl acetate/DCM) to provide a red oil (10 mg).
Example 56
Analytical data for the compounds described is summarized in the table below:















Mass



Exam-
NMR Spectrum δH (400 MHz;
Spectrum
M. Pt.


ple
CDCl3; Me4Si),
(m/z)
(° C.)







21
4.82(2H, d), 6.76(1H, br s),
321(100%,
162-164



7.23(4H, m), 7.48(1H, s), 7.54(2H,
[M+H]+)



m), 7.65(1H, dd), 8.43(1H, m),



8.49(1H, s).


22
4.85(2H, d), 6.75(1H, br s),
303(37%,
121-123



7.20(1H, m), 7.30(1H, s), 7.50(6H,
[M+H]+)



m), 7.65(1H, dd), 8.35(1H, d),



8.45(1H, s).


23
4.80(2H, d), 6.80(1H, br s),
337(100%,
163-164



7.20(1H, m), 7.25(1H, m), 7.50(5H,
[35Cl,



m), 7.65(1H, dd), 8.40(1H, d),
M+H]+)



8.50(1H, s).


24
3.85(3H, s), 4.00(3H, s),
363(100%,
146-148



4.80(2H, d), 6.85(1H, br s), 7.00(1H,
[M+H]+)



d), 7.05(2H, m), 7.15(1H, m),



7.25(1H, d), 7.45(1H, s), 7.65(1H,



m), 8.40(1H, m), 8.50(1H, s).


25
4.85(2H, d), 6.07(2H, s),
347(100%,
186-188



6.82(1H, br s), 6.96(1H, d), 7.03(2H,
[M+H]+)



dd), 7.19(1H, dd), 7.27(1H, m),



7.45(1H, s), 7.66(1H, m),



8.46(2H, s).


26
2.43(3H, s), 4.77(2H, d),
317(100%,
124-128



6.41(1H, br s), 7.14(1H, m),
[M+H]+)



7.22(1H, m), 7.49(5H, m), 7.61(1H,



m), 8.35(1H, d), 8.41(1H, s).


42
3.77(8H, m), 4.76(2H, d),
388(100%,
112-114



6.22(1H, br s), 7.16(1H, m),
[M+H]+)



7.24(2H, m), 7.49(5H, m), 7.65(1H,



m), 8.44(1H, d).


43
3.81(4H, m), 3.91(4H, m),
406(100%,
oil



4.30(2H, br s), 4.71(2H, d), 6.50(1H,
[M+H]+)



br t), 7.17(1H, m), 7.26(2H, m),



7.49(5H, m), 7.64(1H, m),



8.40(1H, d).


41
3.38(3H, s), 3.60(4H, m),
376(100%,
96-98



4.76(2H, d), 5.25(1H, br t), 6.24(1H,
[M+H]+)



br s), 7.17(2H, m), 7.25(1H, m),



7.48(5H, m), 7.62(1H, m),



8.42(1H, d).


44
3.85(2H, br s), 3.90(4H, d),
392(100%,
oil



4.12(1H, m), 4.70(2H, d), 5.72(1H,
[M+H]+)



d), 6.41(1H, br s), 7.15(2H, m),



7.24(1H, m), 7.46(5H, m),



7.62(1H, m), 8.38(1H, d).


46
3.17(6H, s), 4.79(2H, d),
346(100%,
108-110



6.07(1H, br s), 7.16(2H, m),
[M+H]+)



7.27(1H, d), 7.41(1H, m), 7.47(2H,



m), 7.54(2H, m), 7.61(1H, t),



8.45(1H, d).


47
2.40(3H, s), 3.19(6H, s),
360(100%,
52-54



4.76(2H, d), 6.14(1H, br t), 6.99(1H,
[M+H]+)



d), 7.05(1H, d), 7.16(1H, s),



7.40(1H, m), 7.50(5H, m).


48
3.21(6H, s), 4.68(2H, d),
335(100%,
—



5.10(1H, br s), 6.17(1H, d), 6.30(1H,
[M+H]+)



m), 7.15(1H, s), 7.33(1H, d),



7.38(1H, m), 7.44(4H, m).


49
2.33(3H, s), 3.15(6H, s),
360(100%,
oil



4.75(2H, d), 5.77(1H, br t), 7.13(1H,
[M+H]+)



m), 7.25(1H, m), 7.39(1H, m),



7.46(4H, m), 7.59(1H, m),



8.42(1H, d).


50
2.30(3H, s), 3.16(6H, s),
378(100%,
107-109



4.73(2H, d), 5.82(1H, br t), 7.20(4H,
[M+H]+)



m), 7.41(2H, m), 7.61(1H, m),



8.41(1H, d).


51
3.44(3H, s), 3.80(2H, t),
377(100%,
97-99



4.56(2H, t), 4.82(2H, d), 6.79(1H, br
[M+H]+)



s), 7.16(1H, m), 7.23(1H, m),



7.34(1H, s), 7.51(5H, m),



7.63(1H, m), 8.38(1H, d).









Example 57
Kv1.5 Autopatch Electrophysiology
Cells stably transfected with cDNA for human Kv1.5 (in pEF6::VA-His-TOPO) were grown in Dulbecco's Modified Eagle media (DMEM) alpha supplemented with 10% Fetal Calf Serum (FCS), 20 μl/ml penicillin (5000 U/ml) streptomycin (5000 μg/ml), 10 μl/ml [100×] glutamine, and blasticidin (7.5 μg/ml).
The external bathing solution contained (in mM): 150 NaCl, 10 KCl, 100 Potassium Gluconate, 3 MgCl2, 1 CaCl2, 10 HEPES, pH 7.4. Patch pipettes were filled with an electrode solution of composition (in mM): 160 KCl, 0.5 MgCl2, 10 HEPES, 1 EGTA, pH 7.4 with KOH.
Compounds were dissolved in DMSO (100%) and made up in the external bather at a concentration of 1 μM. All experiments were conducted at room temperature (22-24° C.).
A cell suspension (10 ml), with a density of 100,000 cells/ml, was aliquoted into a 15 ml centrifuge tube and transferred to an incubator (37° C., 5% CO2) for approximately one hour before use. Following 60 min incubation, a tube was taken and centrifuged at 1000 rpm for 4 mins at room temperature. 9.5 ml supernatant was thene discarded, leaving a cell pellet at the bottom of the tube. The pellet was then resuspended using 100 μl of cold (4° C.), filtered (0.22 μm), 0.2% BSA/bather solution (0.02 g BSA/10 ml bather). The bottom of the tube was manually agitated gently until the solution became cloudy with cells. The 100 μl cell resuspension solution was then stored on the bench at 4° C. (using a Peltier-based temperature control device) until used.
A length of capillary glass (1B150F-4, WPI) was dipped into the cell suspension solution, such that  ̃3 cm column of fluid was taken up by capillary action. An Ag/AgCl wire was dropped into the non-dipped end of the capillary also. The outside of the solution-filled end of the capillary was then dried and the capillary was loaded into the AutoPatchTM.
Borosilicate glass patch pipettes (from 1.5 mm OD, thin-walled filamented, GC150-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 remain at the tip or in the body of the pipette. Patch pipettes typically had resistances of 2.3-3.5 MΩ. Once filled, the pipette tip and a proportion of the shaft ( ̃15 mm) were dipped into Sigmacote (Sigma). The recording pipette was then loaded into the AutoPatchTM. Automated patch-clamping was initiated by the operator, but thereafter AutoPatch.exe continued the experiment providing that pre-set conditions and criteria were satisfied.
Whole cell patch-clamp recordings were made using the AutoPatchTM rig, which incorporated an EPC9 amplifier (HEKA, Germany) under control of Pulse software (v8.54, HEKA, Germany), a motion controller with 2 translators (Newport, UK), valve controller (VF1) and a c-level suction device all at room temperature (22-24° C.). This equipment was completely under the control of AutoPatch.exe and operator intervention was only made when there was a requirement to refill the drug reservoirs or to prevent the loss of a cell due to a technical error. Cells with an Rseries greater than 18MΩ were discounted from the experiment.
Qualification stages prior to perfusion and drug application ensured that the observed current met the criteria for the experiment. Only those cells with an IK>500 μA were used for experiments. Cells were continuously perfused with external solution at a flow rate of 1.8-2 ml/minute. The perfusion chamber had a working volume of 80-85 μl and allowed for rapid exchange of drug solutions. Online analysis of the hKv1.5 current during the application of compounds was performed by the AutoPatchTM software.
Electrophysiology voltage-step protocols and analysis of data was performed as follows. Data was sampled at 5 kHz, and filtered with a −3 dB bandwidth of 2.5 kHz. Cells were held at a voltage of −80 mV. Currents were evoked to a voltage step for 1000 ms in duration at 0 mV every 5 s. Currents were analysed using Pulsefit software (v8.54, HEKA, Germany), with the total charge measured during the whole of the voltage step. All other plots were produced using Igor Pro (WaveMetrics).
Kv1.5 channel electrophysiology data for the representative compounds described within are given in the table below.














% Inhibition


Example
Compound
@1 (μM)

















21
5-(4-Fluorophenyl)-N-(pyridin-2-
39.76



ylmethyl)furo[2,3-d]pyrimidin-4-amine


22
5-Phenyl-N-(pyridin-2′-ylmethyl)furo[2,3-
54.00



d]pyrimidin-4-amine


23
5-(4-Chlorophenyl)-N-(pyridin-2′-
83.80



ylmethyl)furo[2,3-d]pyrimidin-4-amine


24
5-(3,4-Dimethoxyphenyl)-N-(pyridin-2′-
15.81



ylmethyl)furo[2,3-d]pyrimidin-4-amine


25
5-(1,3-Benzodioxol-5′-yl)-N-(pyridin-2′-
65.17



ylmethyl)furo[2,3-d]pyrimidin-4-amine


26
6-Methyl-5-phenyl-N-(pyridin-2′-
83.00



ylmethyl)furo[2,3-d]pyrimidin-4-amine


42
(2-Morpholin-4-yl-5-phenyl-furo[2,3-
99.00



d]pyrimidin-4-yl)-puridin-2-ylmethyl-amine


43
2-((2-Hydroxyethyl)-{5-Phenyl-4-
82.00



[(pyridine-2-ylmethyl)-amino]-furo[2,3-



d]pyrimidin-2-yl}-amino)-ethanol


41
N2-(2-Methoxyethyl)-5-phenyl-N4-pyridin-
99.00



2-ylmethyl-furo[2,3-d]pyrimidine-2,4-



diamine


44
2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-
75.00



amino]furo[2,3-d]pyrimidin-2-ylamino}-



propane-1,3-diol


46
N2,N2-Dimethyl-5-phenyl-N4-pyridin-2-
99.00



ylmethyl-furo[2,3-d]pyrimidine-2,4-



diamine


45
2-((2-Hydroxyethyl)-{5-(4-fluorophenyl)-4-
42.00



[(pyridine-2-ylmethyl)-amino]-furo[2,3-



d]pyrimidin-2-yl}-amino)-ethanol


47
N2,N2-Dimethyl-N4-(6-methyl-pyridin-2-
98.00



ylmethyl)-5-phenyl-furo[2,3-d]pyrimidine-



2,4-diamine


48
N4-Furan-2-ylmethyl-N2,N2-dimethyl-5-
98.00



phenyl-furo[2,3-d]pyrimidine-2,4-diamine


49
6,N2,N2-Trimethyl-5-phenyl-N4-pyridin-2-
75.00



ylmethyl-furo[2,3-d]pyrimidine-2,4-



diamine


50
5-(4-Fluorophenyl)-6,N2,N2-trimethyl-N4-
32.00



pyridin-2-ylmethyl-furo[2,3-d]pyrimidine-



2,4-diamine


51
[2-(2-Methoxyethoxy)-5-phenyl-furo[2,3-
99.00



d]pyrimidin-4-yl]-pyridin-2ylmethylamine









Abbreviations

















KV(ur)
Cardiac Ultrarapid Delayed Rectifier



CHO
Chinese Hamster Ovary Cells



DMEM
Dulbecco's Modified Eagle media



FCS
Fetal Calf Serum



EBSS
Earls Balanced Salt Solution



WCPC
Whole-Cell Patch-Clamp










It is to be appreciated that the Detailed Description section, and not the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections may set forth one or more but not all exemplary embodiments of the present invention as contemplated by the inventor(s), and thus, are not intended to limit the present invention and the appended claims in any way.
Having now fully described this invention, it will be understood by hose of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any embodiment thereof. All patents and publications cited herein are fully incorporated by reference herein in their entirety.
References
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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 AVEO118 in anesthetized pigs. Cardiovasc Res. November 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), 2235-2242, 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, 1995.
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 et al., “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.
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## Claims

1. A compound of formula




wherein
R1 is aryl, heteroaryl, or cycloalkyl, each of which is optionally substituted;
R2 is H, optionally substituted alkyl, nitro, CO2R7, CONR4R5 or halo;
R3 is H, NR4 R5, NHC(O)R8, halo, trifluoromethyl, optionally substituted alkyl, cyano or alkoxy;
R4 and R5 may be the same or different, and may be H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted 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 optionally substituted 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, each of which is optionally substituted;
or pharmaceutically acceptable salts thereof;
provided that the compound is not 4-diethylamino-5-phenylfuro [2,3-d]pyrimidine.

2. A compound according to claim 1 wherein R1 is optionally substituted aryl or optionally substituted heteroaryl, R2 is H or optionally substituted alkyl, R3 is H, NR4R5, alkoxy or optionally substituted alkyl, X is O or NR6, R6 is H, n is 1 or 2 and Y is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.

3. A compound according to claim 2 wherein R1 is optionally substituted aryl or optionally substituted heteroaryl, R2 is H or methyl, R3 is H, NR4R5, alkoxy or optionally substituted alkyl, X is NR6, R6 is H, n is 1 and Y is optionally substituted aryl or optionally substituted heteroaryl.

4. A compound according to claim 1 wherein Y is phenyl, furanyl, thienyl or pyridyl, each of which is optionally substituted.

5. A compound according to claim 1 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-ylmethyl)furo[2,3-d]pyrimidin-4-amine,
5-(4-Chlorophenyl-N-(pyridin-2-ylmethyl)furo[2,3 -d]pyrimidin-4-amine,
6-Methyl-5-phenyl-N-(pyridin-2-ylmethyl)furo[2,3-d]pyrimidin-4-amine,
(2-Morpholin-4-yl-5-phenyl-furo[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine,
2-((2-Hydroxyethyl)-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-furo[-2,3-d]pyrimidin-2-yl }-amino)-ethanol,
2-((2-Hydroxyethyl)-{5-(4-fluorophenyl)-4[(pyridin-2-ylmethyl)-amino]-furo[2,3-d]pyrimidin-2-yl}-amino)-ethanol,
N2-(2-Methoxyethyl)-5-phenyl-N4-pyridin-2-ylmethyl-furo[2,3-d]pyrimidine-2,4-diamine,
2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino] furo[2,3-d]pyrimidin-2-ylamino}-propane-1,3-diol,
N2,N2-Dimethyl-5-phenyl-N4-pyridin-2-ylmethyl-furo[2,3-d]pyrimidine-2,4-diamine,
N2,N2-Dimethyl-N4-(6-methyl-pyridin-2-ylmethyl)-5-phenyl-furo[2,3-d]pyrimidine-2,4-diamine, or
[2-(2-Methoxyethoxy)-5-phenyl-furo [2,3-d]pyrimidin-4-yl]-pyridin-2-ylmethylamine.

7. A process for preparing a compound according to claim 1 comprising:
(i) reacting a compound of formula II




with a suitable nucleophile X-L-Y, optionally in the presence of a solvent and a base, and optionally at elevated temperature or with microwave irradiation; or
(ii) reacting a compound of formula VI




by displacement of the 2-methanesulphonyl substituent with a suitable nucleophilic species; or
(iii) reacting a compound of formula X




by displacement of the 4-chloro substituent with a suitable nucleophilic species.

8. A pharmaceutical composition comprising at least one compound according to claim 1 and one or more excipients, diluents, carriers, and mixtures thereof.

9. A pharmaceutical composition comprising a compound according to claim 6 and one or more excipients, diluents, carriers, and or mixtures thereof.

10. A method of treating arrhythmia, comprising administering to a subject an effective amount of at least one compound according to claim 1.

11. A method of treating arrhythmia, comprising administering to a subject an effective amount of at least one compound according to claim 6.

12. A compound according to claim 2, wherein Y is phenyl, furanyl, thienyl, or pyridyl.

13. A compound according to claim 3, wherein Y is phenyl, furanyl, thienyl, or pyridyl.

14. A compound according to claim 2, wherein Y is optionally substituted phenyl, optionally substituted furan-2-yl, or optionally substituted pyridin-2-yl.

15. A compound according to claim 2, wherein Y is optionally substituted phenyl, optionally substituted furan-2-yl, or optionally substituted pyridin-2-yl and R6 is H.

16. A compound according to claim 3, wherein Y is optionally substituted phenyl, optionally substituted furan-2-yl, or optionally substituted pyridin-2-yl.

17. The process according to claim 7, wherein the compound prepared is selected from the group consisting of
5-Phenyl-N-(pyridin-2-ylmethyl)furo[2,3-d]pyrimidin-4-amine,
5-(4-Chlorophenyl-N-(pyridin-2-ylmethyl)furo[2,3 -d]pyrimidin-4-amine,
6-Methyl-5-phenyl-N-(pyridin-2-ylmethyl)furo[2,3-d]pyrimidin-4-amine,
(2-Morpholin-4-yl-5-phenyl-furo[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine,
2-((2-Hydroxyethyl)-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-furo[2,3-d]pyrimidin-2-yl }-amino)-ethanol,
2-((2-Hydroxyethyl)-{5-(4-fluorphenyl)-4[(pyridin-2-ylmethyl)-amino]-furo[2,3-d]pyrimidin-2-yl}-amino)-ethanol,
N2-(2-Methoxyethyl)-5-phenyl-N4-pyridin-2-ylmethyl-furo[2,3-d]pyrimidine-2,4-diamine,
2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]furo[2,3-d]pyrimidin-2-ylamino}-propane-1,3-diol,
N2,N2-Dimethyl-5-phenyl-N4-pyridin-2-ylmethyl-furo[2,3-d]pyrimidine-2,4-diamine,
N2,N2-Dimethyl-N4-(6-methyl-pyridin-2-ylmethyl)-5-phenyl-furo[2,3-d]pyrimidine-2,4-diamine, and
[2-(2-Methoxyethoxy)-5-pheny-furo[2,3-d]pyrimidin-4-yl]-pyridin-2-ylmethylamine.

18. A compound according to claim 1 wherein R1 is aryl, heteroaryl or cycloalkyl, each of which is unsubstituted.

19. A compound according to claim 1 wherein Y is heteroaryl, alkyl, alkenyl or cycloalkyl, each of which is unsubstituted.

20. A compound according to claim 1 wherein R6 is H.