| Title of Invention | "THIENOPYRIMIDINE DERIVATIVES AS POTASSIUM CHANNEL INHIBITORS" |
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| Abstract | The present invention provides thienopyrimidine compounds which are potasium channels inhibitors. Pharmaceutical compositions comprising the compounds and their use in the treatment of arrhythmia are also provided. |
| Full Text | THIENOPYRIMIDINE DERIYATIVKfi AS POTASSIDM CHANNEL INHIBITORS The present invention relates. to tnienopyrimidine compounds which are potassium channel inhibitors. Pharmaceutical compositions comprising the compounds and their use in the treatment of arrhythmia are also provided. Ion channels are proteins that spân the lipid bilayer of the cell membrane and provide an aqueous pathway through which specific ions such as Na4", K1", Ca2"1" and CI' can pass (Herbert, 1998). Potassium channels represent the largest and most diverse sub-group of ion channels and they play a central role in rcgulating the membrane potenţial and controlling ccllular excitability (Armstrong & Htlle, 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 arcaş 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, KCNQl/minK, and Kvl.5 are involved in the repolarisation phase of the action potenţial in cardiac myocytes. These potassium channels subtypes have been associated with cardiovascular diseases and disorders including long QT syndrome, hypertrophy, ventricular fibrillation, and atrial fibrillation, all of which can căuşe cardiac failure and fatality (Marban, 2002). The human delayed rcctifier voltage gated potassium channel subunit, Kvl.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 Kvl.5 underlies the cardiac ultrarapid delayed rectifier (Kv^) physiological current in humans due to similar biophysical and phannacological properties (Wang et al, 1993; and Fedida et al., 1993). This nas been supported with antisense oligonucleotides to Kvl.5 which have been shown to reduce Kv(Urj amplitude in human atrial myocytes (Feng et al., 1997). (ii) electrophysiological recordings have demonstrated tfaat Kv(ttr) is selectively expressed in atiial myocytes, and therefbre 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 fibriUation-type human atrial myocytes prolonged the action potenţial duration compared to normal healthy human atrial myocytes (Courtemanche et al, 1999). (iv) Prolonging the action potenţial duration by selectively inhibiting Kvl.S could present safer pharmacological interventions for protecting against atrial re-entrant arrhythmias such as atrial fibrillation and atrial flutter compared to tradiţional class m ana'arrythmics, by prolonging the atrial refractory period while leaving ventricular refractorincss unaltered (Nattel et ai., 1999, Knobloch et al., 2002; and Wirth et al., 2003). Class m antian^mniics have been widely reported as a preferred method for treating cardiac arrhythmias (Cdatsky et al, 1990). Tradiţional and novei clus OI antiarrythmic potassium channel blockers have been reported to have • mectuaism of action by directly modulating Kvl.S or Kv(Dr). The known class m antiarrythmics ambasilide (Feng et al. , 1997), quinidine (Wang et al., 1995), clofiliura (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 novei benzopynn derivative, NDM42, blocks Kvl.S channels, prolongs the atrial refractory period and terminatos atrial fibrillation and flutter in in vivo canine models (Matsuda et al., 2001), and S9947 inhibited Kvl.S stably expressed in both Xenopus oocytes and Chinese hamster ovary (CHO) cells and KV(ur) in native rât and human cardiac myocytes (Bachmann et al, 2001). Elsewhere, other novei potassium channel modulators which target Kvl.S 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), betvzopyran derivatives (WO0121610, WO03000675, WO0121609, WO0125224, WO02064581), benzoxazine derivatives (WO0012492), and the novei compound A1998 purified from Ocean material (Xu & Xu, 2000). Thienopyrimidines have been rcported to be useful as anti-inflammatory, anti-fungal, anti-osteoporosis and and-microbial agents amongst others. Although also reporteri as cardiovascular agents (acting through modulation of the phosphodiesterase group of enzymes or through modulation of the sodium/proton exchange system), thienopyrimidines have not previously been reported as useful agents for modulating ion channels. Thieno[2,3- heterocyclyl, amino, methyl, cthyl or phenyl group in the 2-position, an alkylamino, alkylarylamino, amino, dialkylamino or hydrazino substituent in the 4-position, a hydrogen or methyl group in the 5-position, a hydrogen, methyl acetamide or phenyl group in the 6-position or a tetramethylene in the 5,6-position (GB7S4902S), and the lead series of 5-phenyl- and 5,6-tetramethylenethieno[2,3-d]pyrimidines with methyl or phenyl in the 2-position and alkylamino or arylamino in the 4- position (Konno ei al., 1989) nave all been shown to have anti-microbial activity. Tetrahydrobenzothieno[2,3-rf]pyrimidine with the 2-oxo-3-pyrrob'dinylmethylene-hydrazino moiety in the 4-position showed some herbicidal activity against velvet leaf (Ram et al., 1981). It has also been reported that 4-chIorotetrahydrobenzothieno[2,3-rf]pyriinidine is herbicidal, tetrahydrobenzothieno-[2,3- Elsewhere, tetrahydrobenzo{b]thieno[2,3-rf]pyrimidines exhibited anti-tumour activity (Shehata et al, 19%) and analgesic activity half mat of aspirin (Moneer et al., 1994), a series of thieno[2,3-d]pyrimidmes with 4-alkylamino or arylamino, 5-H or 5-methyl, 6-methyl or 5,6-tetramethylene were shown to have potenţial as anticytokinins (Jordis et al., 1986), a series of 5,6-dimethyl-mieno[2,3-d]pyrimidines and 5,6-tetramethylenethieno[2,3-d]pyrimidines, both substituted in the 2-position with arylamines or heterocyclic amines and in the 4-position with arylamines displayed blood platelet aggregation iahibiting properties (DD 226893), pyrano- and thiopyrano[3,4-b]thieno[5,4-d3pyrimidines with tiîe 4-position substituted with amino, butylamine, aniline, cyclohexylamine, benzylamine, phenethylamine and 2-hydroxyethylamine have been reported to exhibit anticonvulsive activity (Noravyan et al., 1977), and 4-[(Benzo- 2,13-^adiazolyW)ainino]-5,6J,8-tetrahydrobenzothieno-(23HO-pyriniidine has been reported to possess anthelmintic activity in larval alveolar echinococcosis (RU 2116309). Thieno[2,3-41pyrimidines with a substituted amino group at the 4-position, hydrogen, alkyl or halo substitution at the 5 and 6-positions and an alkyl chain at the 2-position are claimed to be inhibitors of phosphodiesterase V and useful in the treatment of cardiovascular diseases and for disturbances in potency (DE10104802). Elsewhere, 5-alkyl thieno[2,3- 44(Phenyl)arnino]-^eno(23-rflpyrirnidines bearing a 5-thiophenyl substituent and a 2-methyl substituent wece found to have molluscicidal activity (Hosni et al, Acta Poloniae Pharmaceutica, 1999,56(1). 49-56). Recently thienopyrimidines have also been reported as potent VEGFR inhibitors (Munchhof, 2004). Severa! publications disclose compounds which are indicated as acting on potassium channels. Thus, US6531495 discloses 2'-aminomethylbiphenyl-2-carboxamides, W02Q02/100825 discloses anthranillic acid amides as antiarrhythmics and WO2002/036556 discloses acylaminoalkylbenzenesulfonamides as cardiovascular agents. This invention provides compounds that are potassium channel inhibitors. These compounds are particularly useful for inhibiting potassium channels Kvl.5 or Kv(Ur), which are known targets for the treatment of cardiac arrhythmia in the atria such as atrial fibrillation (Nattel et cd., 1999; Wang et al, 1993). This invention is not limited to treating cardiac arrhythmias, the compounds also being useful to treat diseases which requirc potassium channel inhibition (e.g. Shieh et al., 2000; Ford et al.t 2002). Thus, in a first aspect, the present invention provides a compound of formula (I) (Figure Removed) Wherein Rl is aryl, heteroaryl, cycloalkyl or alkyl; R2 is H, alkyl, nitro, COaR, C(O)NR4R5 or halo; R3 is H, NR4RS, NC(O)R8, halo, trifluoromethyl, alkyl, nitrile or alkoxy; R4 and RS may be the same or different, and may be H, alkyl, aryl, heteroaryl or cycloalkyl; or R4 rad 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; XisO,SorNR6; R6isHoralkyl; R7 is hydrogen, methyl or ethyl; RSismethyloremyl; L is (CHj),,, where n is l, 2 or 3; and Y is aryl, a heterocyclic group, alkyl, alkenyl or cycloalkyl; or pharmaceutically acceptable salts thereof; with the proviso that when Y is phenyl, phenyl monosubstituted by CI or methoxy, furanyl, tetrahydrofurayl, pyrimidinyl, pyrrolidinyl or 1,3-benzodioxolyl, then Rl is not phenyl, phenyl monosubstituted by halogen or phenyl substituted by methyl; and wherein the compound is not: N-Butyl-5-phenylthieno[2,3-d]pyrimidin-4-amine; 5-Phenyl-N-(pyridin-2-ylmethyl)thieno[2,3-d]pyrimidin-4-anune; 5-(4-Chlorophenyl)-N-[3-(lH-inu'da2X)l-l-yl)propyl]thieno[2,3^]pyrimidin-4-amine; 5_(4_Chlorophenyl)-N-(pyridin-2-ylmethyl)thieno[2,3-d]pyrimidin-4-amine; 5-(4-Chlorophenyl)-N-(2-cyclohex-l-en-l-yl^iyl)thieno[2,3-d]pyrimidin-4-amine; 5-(4-Chlorophenyl)-N-(pyridin-3-ylmethyl)thienot23^]pyrinunainine; 5-(4-Chlorophenyl)-N2-fvirylmelhyl)thieno[23]pyriniidin-4-amine; N-Allyl-5-phenylthieno[2,3-d]pyrimidin-4-amine; 5-(4-MeAylphenyl)-N-(2-tiiien-2-yl^yl)tMeno[23^]pyriniidin-4-aiiiine; N-(2-Ptuylmethyl)-5-phenylthieno[2,3-d]pyrimidin-4-amine; 5-(4-Chl(MophOTyl)-N-(2-thien-2-ylethyl)tWeno[23^]pyrimidin-4-amine; 5-(4-Huorophenyl)-N-(2-thien-2-ylcthyl)fliieno[2,3-d]pyrimidin-4-amine; N-Allyl-5-(4-chlorophenyl)thieno[2,3-d]pyriniidin-4-amine; yl)-N-(tett^ydrofuran-2-ylinefo M-(tetrahydrotui»n-2-yl N-[3-( IH-îmidazol- l-yl)pn^y!3-5-phrayltfaetK)[2,3Mi]pyriniidin-4-ainine; !-(2-{[5-(4-MethylphenyI)thieno[2,3^]pyrinM or N^-FurylmethylJ-S^-meUiylphenyOthienop.S-djpyrimidin-^amine. As used herein, an alkyl group or moiety is typically a linear or branched alkyl group or moiety containing frora l to 6 carbon atoms, such as a Q-CU alkyl group or moiety, for example rnethyl, ethyl, n-^propyl, i-propyl, butyl, imtyl 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, COzR7, C(O)NR9R10, NC(O)R8 and SOaNRSRlO. As used herein, an aryl group is typically a Cg-Cio aryl group such as phenyl or napthyl. A preferred aryl group is phenyl. An aryl group may be unsubstituted or substituted at any position. Typicaiiy, it carries i, 2, 3 or 4 substituents. Suitable substitaents include cyano, halogen, nitro, trifluoromethyl, alkyl, alkylthio, 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 S- to 10- membercd 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, COzR7, C(O)NR9R10, NC(O)R8 and SO2NR9R10 and hydroxyl. R9 and RIO can be the same or different, and may be selected from H, unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl, aminoethyl, methylaminoethyl, dimethylaminocthyl, hydroxyethyl, alkoxyethyl, or R9 and RIO may together form a saturated, unsaturated or para'ally saturated 4 to 7 member ring. When R4 and R5 or R9 and RIO 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 Cu alkoxy, cycloalkyl means C^ cycloalkyl and halogen means CI, F, Br, or I, preferably CI, F or Br. Preferred compounds of formula I are those wherein Rl 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 l or 2 and Y is alkyl, cycloalkyl, aryl or heteroaryl. More preferred compounds of fonnula I are those wherein Rl is aryl or heteroaryl, R2 is H or methyl, R3 is H, NR4R5, alkoxy or alkyl, X is NR6, R6 is H, n is l and Y isheteroaryl. Preferably Y is fiiranyl, tfrienyl or pyridyl. Morc preferably Y is optionally substituted furan-2-yl or optionally substituted pyridin-2-yl. Preferred compounds include: 2-{5-Phenyl^[(pyridin-2-yln»thyl)-amino]-thieno[2,3^]pyrinridin-2-yl}-propane-l,3- diol; 2-{5^4-Huorophenyl)^-[(pyridin-2-ylmethyl)-amino]-tWeno[2,3^]pyrimidin-2- ylaminoj-ethanol; Pyridln-2-ylmethyH5-p-tolyl-thieno[2^-d]pyriniidin-4-yl)-amine; 2-{5-Phrayl^[(pyridin-2-ylmeAyl)-amino]-thieno[23^]pyrimidin-2-ylamino}-ethanol; 2-{ 5-PhenyM-[(pyridin-2-ylmethyl)amino]thieno[2,3- 2-yl}-amino)-ethanol; 2-Methyl-N [2 amine; (2-Methoxy-5-phenyl-thi«io[23^3pyrinudin-4-yl)-pyridin-2-ylmethyl-aniine; 5 d]pyrimidine-2,4-diamine; l-N— pyridin-2-ylmethyl-thieno[2,3^]pyrimidine-2,4-diamine; Pyridin-2-ylmelhyl-[5-(4-trifluoromethyl-phenyl)-tWeno[2,3-d]pyrinudin^-yl]-amin^ [5-(lH-Indol-6-yl)-Meno[23-d]pyriniidin-4-yl]-pyridin-2-ylmethyl-amine-, (5-Benzo[13]dioxol-5-yI-thieno[2,3-dlpyriinidin-4-yl)-pyridin-2-ylmethyl-amine; 2-{ 5-Pheny W-[(pyrid^n-2-ylmethyl>amno]-thieno[23-d]pyrinudin-2-ylaiiuno } -propane-l,3-diol; propane-l,2-diol; N-Methyl-2-{5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-d]pyrimidin-2- yl}acetamide;or 6-Melhyl-N-[(6-methylpyridin-2-yl)methyl]-5-phenylthieno[2,3-d]pyrimidin-4-ainine; and pharmaceutically acceptable salts thereof. Compounds of formula I wherein R3 is H, alkyl or trifluoroalkyl are synthesised from a compound of formula n by reaction with a suitable nucleophile X-L-Y, where X, Y and L are as defined herein, optionally in the presence of a solvent and a basc, and optionally at elevated temperature or with microwave irradiation. Preferably the solvent (if present) is an alcohol, preferably ethanol, and the basc is a hindered nitrogen base such as triethylamine. If a solvent is present the reaction is carried out at the reflux temperature of the solvent, or under sealed conditions and with microwave irradiation at a temperature of 120-160°C. (Figure Removed) A compound of formula n may be obtained from a compound of formula HI by reaction with a chlorinating reagent such as phenylphosphonic dichloride or phosphorous oxychloride in a suitable solvent or no solvent, and with heating. Preferably the chlorinating reagent is phosphorous oxychloride and the reaction is carried out at reflux temperature and in the absence of additional solvent. (Figure Removed) Compounds of formula DI raay be obtained by the reaction of a compound of formula IV with a suitable substituted or unsubstituted amidine of formula V, or its salt equivalent. The reaction may be camed out in the presence of a suitable solvent at elevated temperature. Preferably the solvent is ethanol and the reaction is camed out under reflux conditions. (Figure Removed) In an alternative synthesis of compounds of formula HI, also applicable to those examples wherein R3 is an alkyl group, reaction of a compound of formula VI under basic conditions in a suitable solvent is performed. Suitable bases include alkali metal alkoxides such as sodium methoxide. Suitable solventa include alcohols such as methano (Figure Removed) A compound of formula VI can be prepared by reaction of a compound of formula VH under acylating conditions, for example in the presence of an acid chloride and a base. Exemplified acid chlorides include acetyl chloride. Suitable bases include the nitrogenous bases such as triethylamine and pyridine. (Figure Removed) Compounds of fonnula VH are widely available firom standard commercial sources or raay be obtained from compounds of fonnula IV by simple funcţional group interconversions. Compounds of formula V are widely available from standard commercial sources or can be synthesised by routine organic chemistry procedures. A compound of fonnula IV can be prepared by reaction of a compound of formula VEI, under basic conditions and in a suitable solvent, with powdered sulphur. Preferably the base is diethylamine and tfae reaction is carried out at 25 to 65°C. The solvent may be an alcohol, preferably ethanol. (Figure Removed) Compounds of formula VIE can be prepared by heating a compound of formula DC with ethylcyanoacetate (NCCHaCOaEt) in the presence of an acid and ammonium acetate in a suitable solvent, optionally with azeotropic water removal. Preferably the acid is acetic acid. (Figure Removed) Compounds of formula IX are widely available fcom commercial sources or can be readily synthesised using standard synthetic organic chemistry procedures. Alternatively, compounds of formula I whercin R3 is otfaer mân H, alkyl or trifluoroalkyl, can be prepared from a compound of formula X by displacement of the 2-chloro substituent with a suitable nucleophilic species. Such a reaction may be carried out with heating or microwave irradiation. (Figure Removed) Compounds of formula X are readily synthesised from compounds of formula XI by reaction 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. Preferably the solvent (if present) is an alcohol, preferably propan-2-ol, and the base is a hindered nitrogen base such as triethylamine. The reaction îs carried out at ambient temperatures. (Figure Removed) A compound of formula XI may be synthesised by reaction of a compound of formula XII with a chlorinating reagent such as phenylphosphonic dichloride or phosphorous oxychloride. (Figure Removed) Compounds of formula XII are available by the reaction of a compound of formula IV with an alkali metal cyanate, preferably potassium cyanate. Altematively, compounds of formula I wherein R3 is an ester-substituted alkyl group, in particular an acetic acid ester, can be prepared by the reaction of a compound of formula XHI, by reaction with a suitable nucleophile X-L-Y optionally in the presence of a solvent and a base, and optionally al elevated temperature or with microwave irradiation. Preferably the solvent (if present) is an alcohol, preferably ethanol, and the base is a hindered nitrogen base such as triethylamine. If a solvent is present the reaction is carried out at the reflux temperature of the solvent, or under sealed conditions and with microwave irradiation at a temperature of 120-160flC. (Figure Removed) Compounds of formula XDI may be synthesized from compounds of formula XIV by reaction with a chlorinating reagent such as phenyiphosphonic dichloride or phosphorous oxychloride. (Figure Removed) Compounds of formula XIV are synthesized by reaction of compounds of formula IV with ethyl cyanoacetate, performed under acidic conditions with or without the presence of solvent. Suitable acids include gaseous hydrogen chloride. It is understood mat compounds of formula I wherein R3 is a carboethoxy group may undergo funcţional 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 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. Compounds of formula I wherein R3 is a chloromethyl group may be synthesized from compounds of formula XV by reaction 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. Preferably the solvent (if present) is an alcohol, preferably propan-2-ol, and the base is a hindered nitrogen base such as triethylamine. The reaction is carried out at ambient temperature. (Figure Removed) Compounds of formula XV may be synthesized from compounds of formula XVI by reaction with a chlorinating reagent such as phenylphosphonic dichloride or phosphorous oxychloride. (Figure Removed) Compounds of formula XVI may be synthesized by reaction of a compound of formula IV under acidic conditions in a suitable solvent with chloroacetonitrile. Suitable acids include gaseous hydrogen chloride. Suitable solvente include alkyl ethers such as 1,4-dioxane. It is understood that compounds of formula I wherein R3 is a chloromethyl group may undergo standard funcţional group transformations of the chloromethyl moiety using methods familiar to those skilled in the art. In a preferred instance reaction with a nucleophile is canied out Suitable nucleophiles may include an alkyl or dialkyl amine, an alcohol or a thiol, or anion derivatives thereof. In an alternative synthesis of compounds of formula I, particularly applicable to those examples wherein Rl comprises an aryl or heteroaryl group, a compound of formula XVn is reacted with an aryl or heteroaryl boronic acid, preferably under coupling conditions such as in the presence of a palladium(0) catalyst, preferably tetrakis(triphenylphosphine) palladium(0) which may be generated in situ or attached to a polymer resin. Alternative coupling conditions will be familiar to those skilled in the art. If a solvent is present the reaction is canied out at the reflux temperature of the solvent, or under sealed conditions and with microwave irradiation at a temperature of 120-160°C. (Figure Removed) A compound of formula XVII may be synthesised from a compound of formula XVIII by reaction 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 iiradiation. Preferably the solvent (if present) is an alcohol, preferably ethanol, and the base is a hindered nitrogen base such as triethylamine. If a solvent is present the reaction is carried out at the reflux temperature of the solvent, or under sealed conditions and with microwave irradiation at a temperature of 120-160°C. (Figure Removed) Compounds of fonnula XVDI whercin R2 is H may be synthesized by reaction of a compound of formula XIX under basic conditions at reduced temperature in a suitable solvent. Preferably the base is an alkyllithium, in the most preferred instance lithium diisopropylamide and the solvent is an alkylether, in the most preferred instance tetrahydrofuran. The reaction may be carried out from -80°C to ambient temperature. (Figure Removed) A compound of formula XIX may be obtained from a compound of formula XX by reaction with a chlorinating reagent such as phenylphosphonic dichloride or phosphorous oxychloride in a suitable solvent or no solvent, and with heating. Preferably the chlorinating reagent is phosphorous oxychloride and the reaction is cartied out at reflux temperature and in the absence of additional solvent. (Figure Removed) Compounds of formula XX may be synthesized by reactions of compounds of formula IU wherein Rl is H and R2 is H with an electrophilic halogenating reagent preferably bromine in a suitable solvent preferably glacial acetic acid. Alternatively, compounds of formula XVm wherein R3 is other than H, alkyl or trifluoroalkyl and R2 is other than hydrogen may be synthesized from compounds of formula XXI by displacement of the 2-chloro substituent with a suitable nucleophilic species. Such a reaction may be carried out with heating or microwave irradiation. (Figure Removed) Compounds of formula XXI are readily synthesised from compounds of formula XXII by reaction 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. Preferably the solvent (if present) is an alcohol, preferably ethanol, and the base is a hindered nitrogen base such as triethylamine. (Figure Removed) A compound of formula XXH may be synthesised by reaction of a compound of formula XXm with a chlorinating reagent such as phenylphosphonic dichloride or phosphorous oxychloride. (Figure Removed) A compound of formula XXffl may be synthesized by reaction of a compound of formula XII wherein Rl is H and R2 is alkyl with an electrophilic halogenating reagent, preferably bromine, in a suitable solvent, preferably glacial acetic acid. Many of the starting materials rcferred to in the leactions descnbed 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 (E), Eds Katritzky, A. R., Rees, C. W., Scriven, E. F. V., (2). 607-678. Suitable starting materials include: (Table Removed) 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 phannaceutical formulation comprising at least one compound and optionally one or more excipients, carriers or diluents; wherein said compound nas the formula: (Figure Removed) Wherein Rl is aryl, heteroaryl, cycloalkyl or alkyl; R2 is H, alkyl, nitro, COJR.7, 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 roethyl or ethyl; L is (CH2)n, where n is l, 2 or 3; and Y is aryl, a heterocyclic group, alkyl, alkenyl or cycloalkyl; or pharmaceutically acceptable salts thereof; with the proviso that when Y is phenyl, phenyl monosubstituted by CI or methoxy, furanyl, tetrahydrofurayl, pyrimidinyl, pyrrolidinyl or 1,3-benzodioxolyI, then Rl is not phenyl, phenyl monosubstituted by halogen or phenyl substituted by methyl. Preferably the compound is a compound as described in the first aspect The compositions of the invention may be presented in unit dose forms containing a predetermined amount of each active ingredient per dose. Such a unit may be adapted to provide 5-100mg/day of the compound, preferably either 5-15mg/day, 10-30mg/day, 25-SOmg/day 40-80mg/day or 60-100mg/day. For compounds of formula I, doses in the range 100-lOOOmg/day «re provided, preferably either 100-400mg/day, 300-600rag/day or 500-lOOOmg/day. Such doses can be provided in a single dose or as a number of discrete doses. The ultimate dose will depend on the condition being treated, the route of administration and the age, weight and condition of the patient and will be at the doc tor'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 mctiiod 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, suspension», lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For applicau'ons to the eye or other externai tissues, for example the mouth and ştia, 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 basc. Alternativcly, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil basc. Pharmaceutical formulations adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable cartier, cspecially 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 cartier is a solid include a coarse powder having a partide size for example in the rang? 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 oii solutions of the active ingredient. Pharmaceutical formulations adapted for administration by inhalation include fine partide 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 parcnteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostatfi 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 agentB and thicfcening agente. The fbnsulations 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 shouid be understood mat in addition to the ingredients particularly mentioned above, the formulations may also include other agents convenţional 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 usc in medicine, wherein said compound has the formula: (Figure Removed) Wherein Rl is aryl, heteroaryl, cycloalkyl or alkyl; R2 is H, alkyl, nitro, COaR?, CONR4R5 or halo; R3 is H, NR4R5, NC(O)R8, halo, ttifluoromethyl, 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 RS 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; XisO,SorNR6; R6isHoralkyl; R7 is hydrogen, methyl or ethyl; R8 is methyl or ethyl; L is (CHa)n, where n is l, 2 or 3; and Y is aryl, a heterocyclic group, alkyl, alkenyl or cycloalkyl; or pharmaceutically acceptable salts thereof; with the proviso that when Y is phenyi, phenyl monosubstituted by CI or methoxy, furanyl, tetrahydrofurayl, pyrimidinyl, pyrrolidinyl or 1,3-benzodioxolyl, then Rl is not phenyl, phenyl monosubstituted by halogen or phenyl substituted by methyl. 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 arrhythmia. Thus, in further aspects, the present invention provides: (i) a method of treating or preventing a disorder which requires potassium channel inhibition, eg antiythmia, 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: (Figure Removed) Wherein Rl is arjd, heteroaryl, cycloalkyl or alkyl; R2 is H, alkyl, nitro, COtftf, CONR4R5 or halo; R3 is H, NR4R5, NC(O)R8, halo, trifluoromethyl, alkyl, nitrile or alkoxy; R4 and RS 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 (CHiJn, where n is l, 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 raanufacture of a medicament for use in potassium channel inhibition; wherein the compound has the formula: (Figure Removed) Wherein Rl is aryl, hetaroaryl, cycloalkyl or alkyl; R2 is H, alkyl, nitto, CQtfil, CONR4R5 or halo; R3 is H, NR4R5, NC(O)R8, halo, trifluoromelhyl, 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; XisO, SorNR6; R6isHoralkyl; R7 is hydrogcn, methyl or ethyl; R8 is methyl or ethyl; L is (CH2)n, where n is l, 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 tbe art using routine experimentation, such as procedures and techniques illustrated herein and described in detail in Ford et al., 2002. Example 1. 2-Cyano-3-phenyl-but-2-enolc acid ethyl ester A stirred mixture of acetophenone (180g, l.Smol), ethyl cyanoacetate (170g, l.Smol), ammonium acetate (23.Ig), acetic acid (72g) and toluene (SOOml) was heated under reflux for 18 hours while watcr was removed from the reaction by azeotropic distillation. The mixture was allowed to cool to ambient temperature, toluene (lOOml) was added, then the mixture was washed with water (3 x lOOml). The combined aqueous washings were shaken with toluene (50ml), then the combined toluene solutions were dried (MgSO4) and the solvent was removed in vacuo. The residual oii was distilled under reduced pressure to give 2-cyano-3-phenyl-but-2-enoic acid ethyl ester as an oii which was used without further purification. Examples 2 to 18 The compounds set out below were prepared in the same way as in Example l, using the appropriate starting materials. (Table Removed) 2-Aminot-phenyl- Aiophene-3-carboxyIic acid ethyl ester 2-Cyano-3-phenyl-but-2-enoic acid ethyl ester (513.25g, 2.3mol) was added at ambient temperature to a vigorously-stirred suspension of powdered sulfur (76g, 2.3mols) in ethanol (SOOml). Diethylamine (200ml) was added in portions over 20 minutes, during which time the temperature of the reaction rose to 62°C. The mixture was allowed to cool to 36°C, then it was heated to 50°C and stirring at that temperature was contmued for l hour. After this time, stirring was discontinued, the hoţ solution was removed by decantation from unreacted sulfur, then it was allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with a little cold ethanol and dried in vacuo to give 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester as an orange solid which was used without further purification. Examples 20 to 36 The compounds set out below were prepared in the same way as in Example 19, using the ppropriate starting materials. (Table Removed) Example 37 5-PhenyI-3H-thieno[2,3-d]pyrimidin-4-one A stirred mixture of 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester (350.43g, 1.535mol), formamidine acetate (799.13g, 7.7mol) and ethanol (ISOOml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with a little cold ethanol, then crystallised frorn ethanol to give 5-Phenyl-3H-thieno[2,3-d]pyrimidin-4-one as a yellow solid which was used without further purifîcation. Examples 38 to 54 The compounds set out below were prepared in the same way as in Example 37, using the appropriate starting materials. (Table Removed) Example 55 2-Methyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one A stirred mixture of 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester (350.43g, 1.54mol), acetamidine hydrochloride (725.13g, 7.676mol) and ethanol (ISOOml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The resulting solid was collected uy Tiltration, washed with a little cold ethanol, then crystallised from ethanol to give 2-Methyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one as a yellow solid which was used without further purification. Example 56 The compound set out below was prepared in the same way as in Example 55, using the appropriate startrag materials. (Table Removed) Example 57 4-pheoyl-2-propionylaminothtophene-3-carboxylic amide A mixture of 2-amino-4-phenylthiophene-3-carix)xylic acid amide (3.0g, 13.8mmol) and anhydrous pyridine (12ml) was treated with propionyl chloride (1.32ml, 15.2mmol) and stirred at ambient tempenture for 3 hours. The excess pyridine was removed in vacue to give a rcsidue, which was treated with ethanol (50ml) and sodium methoxide (2.24g, 41.4mmol) and the resultant mixture was heated under reflux for 18 hours. The cooled mixture was then diluted with water (300ml) and acidified with concentrated hydrochloric acid. The resulting solid was collected by filtration, washed with water and dried in vacuo to give 4-phenyl-2-propionylaminothiophene-3-carboxylic amide. Example 58 2-ethyl-5-phenyl-3H-tnieno[2,3-rf]pyrimidin-4-one The solid 4-phenyl-2-propionylaminothiophene-3-carboxylic amide was added to a mixture of ethanol (50ml) and sodium methoxide (2.24g) and the resultant mixture was heated under reflux with stirring for 18 hours. The cooled mixture was diluted with water (300ml) and acidified with concentrated hydrochloric acid. The resulting solid was collected by filtration, washed with water followed by acetonitrile and dried in vacuo to give 2-emyl-5-phenyl-3/f-thieno[2,3-d]pyriniidin-4-one (2.38g), which was used without further purification. 5-PhenyI-2-trifluoromethyl-3H-thierio[2-d]pyrimidin-4-one A stirred mixture of 2-amino-4-phcnylthiophene-3-carboxylic acid ethyl ester (350.43g, 1.535mol), trifluoromethylacetamidine hydrochloride (1167.36g, 7.676mol) and ethanol (ISOOml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with a little cold ethanol, then crystallised from ethanol to give 5-Phenyl-2-trifluorDmethyl-3H-thieno[2,3-d]pyrimidin-4-one as a yellow solid which was used without further purification. 2-IsopropyI-5-phenyl-3H-liileao[2-d]pyriinidin-4-oDe A stined mixture of 2-anuno-4-phenylthiophene-3-carboxylic acid ethyl ester (350.43g, 1.54mol), isopropylacetamidinc hydrochloride (958.75g, 7.7mol) and ethanol (ISOOml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with a little cold ethanol, then crystallised from ethanol to give 24sopropyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one as a yellow solid which was used without further purification. Examplc61 4-Chloro-5-phenyl-thieno[2-d]pyrimidine 5-Phenyl-3H-thieno[2,3-d]pyrimidin-4-one (294.6g, 1.29mol) was added in portions to stirred phosphoryl chloride (lOOOml), then the stirred suspension was warmed gently to reflux temperature, heated under reflux for 4 hours, and allowed to stand at ambient temperature for 18 hours. The resulting dark solution was removed by decantation from a solid residue and concentrated in vacuo to give a gummy solid. The two solids were combined and added to crushed ice (lOOOml). The product was extracted into dichloromethane (3 x SOOml), then the combined extracts were washed with water (2 x 300ml) and saturated aqueous sodium hydrogen carbonate solution (SOOml) and dried and decolourised (MgSO4 4- charcoal). The solvent was removed in vacuo to give 4-Chloro- Examples 62 to 82. The compounds set out below were prepared in the same way as in Example 61, using the appropriate starting materials. (Table Removed) Example83 Furan-2-ylmethyl-(5-phoiyl*tbieno[2^d]pyrimidin-4-yl)-amine A stibcied mixture of 4-chloro-5-phenylUueno[2,3-d]pyrimidine (2.2g, O.OOPmol), furfurylamine (1.26g, 0.013mol), triethylamine (1.3g) and ethanol (20ml) was heated under reflux for 2 hours then cooled to ambient temperatura and poured into water (50ml). The resulting solid was collected by filtration, washed with water (30ml), dried in vacuo and crystallised from a mixture of hexane and toluene to give furan-2-ylmethyl-(5-phenyl-thieno[23^}pyiimidin-4-yl)-ainine as a pale yellow solid, m.pt. 77-79°C. Examples 84 to 100 The compounds set out below were prepared in the same way as in Example 83, using the appropriate starting materials. (Table Removed) Example 101 2-Methyl-N-(2-pyridyl)methyl-5-phenyIthieno[2^-d]pyrimidin-4-ylamine In a 10 ml glass tube were placed 2-methyl-4-chloro-5-phenylthieno[2,3-d]pyrimidin-4-ylamine (0.076g, 0.293 mmol), 2-(aminomethyl)pyridine (0.0364g, 0.03mmol) and ethanol (2.5ml). The vessel was sealed with a scptum and placed in the microwave cavity. Microwave irradiation of 200W was used, the temperature being ramped from room temperature to 150°C. Once 150°C was reached, the reaction mixture was held at this temperature for 10 minutes. After cooling to ambient temperature, water (4ml) was added and the mixture stirrcd for 2.5 hours. The resulting solid was collected by fîltration, washed with water and dried in vacuo to give 2-methyl-N-(2-pyridyl)methyl-5-phenyltrueno[2,3Hi3pyrimidin-4-ylarfline (0.084g) as an off white solid, m.pt. 110-112°C. Examples 102 to 167 The compounds set out below were prepared in the same way as in Example 101, using the appropriate starting materials. (Table Removed) 5-Phenyl-lH-thieno[23^]pyrimidine-2,4-dione A mixture of ethyl 2-amino4-phenyl4Mophene-3-carboxylate (2.0g, 8.1 mmol) and potassium cyanatc (2.0g, 24.3 mmol) in glacial acetic acid (20ml) was stirred at ambient temperatura for 72 hours. The resultant solid material was filtered off. The filtrate was diluted with water (SOml) and the precipitated solid was filtered off. The two solids were combined, suspended in water (lOOml) and made alkaline by the addition of concentrated sodium hydroxide solution. The resultant suspension was heated at 100°C for 2 hours with stirring, then allowed to cool to ambient temperature and acidified by the addition of glacial acetic acid. The resulting solid was collccted by filtration to give 5-phenyl-l,3#-thieno[2,3-rf]pyriinidin-2,4-dione (l.lg) as a white solid which was used without further purification. Examples 169 to 174 The compounds set out below were prepared in the same way as in Example 168, using the appropriate starting materials. (Table Removed) Example 175 2,4-Dichloro-5-phenyl-thieno£2^-d]pyrimidine A stirred mixture of 5-phenyl-l,3flr-thieno[2,3- Examples 176 to 180 The compounds set out below were prepared in the same way as in Example 175, using the appropriate starting materials. (Table Removed) Example 181 (2-Chloro-5-phenyNtfaieno[2>dîPyrimidin-4-yl)-pyrklin-2-ylmethyl-amine A mixture of 2,4-dichloro-5-phenyl-thieno[2,3-rf]pyrimidine (0.82g, 2.92 mmol), 2-(aminomethyOpyridine (0.35g, 3.21 mmol), triethylamine (0.32g, 0.45ml, 3.21 mmol) and propan-2-ol (20 ml) was stirred at ambient temperature for 72 hours. Water (50ml) was added to the reaction mixture and the organic phase was extracted using dichloromethane (3 x 50ml), The combined extracts were washed with water and dried (MgSO/t). The solvent was removed in vacuo to give 2-chloro-//-(2-pyridyl)methyl-5-phenylthieno[2,3-d]pyrimidin-4-ylamine (l.Og) as a white solid which was used without further purification. Examples 1Ş2 to 187 The compounds set out below were prepared in the same way as in Example 181, using tbe appropriate starting materials. (Table Removed) Example 188 N2-Cydopropylmetlţyl-5-i^ diamine In a 10 ml glass tube were placed 2-chloro-JV-(2-pyridyl)methyl-5-phenylthieno[2,3-d]pyrimidin-4-ylamine (0.03g, 0.0852 mmol) and cyclopropylmethylamine (O.Sml). The vessel was sealed with a septum and placed m the microwave cavity. Microwave irradiation of 200 W was used, the temperature being ramped from room temperature to 200°C. Once 200°C was rcached, the reaction mixture was held at this temperature for 40 minutes. After cooling to ambient temperature, water (4ml) was added and the mixture stirred for 2.5 hours. The resulting solid was collected by filtration, washed with water and dried under reduced pressure to give N2-Cyclopropylmethyl-5-phenyl-N4-pyridin-2-ylmethyl-thieno[2,3-d]pyrimidine-2,4-diamine (0.025g) as a yellow solid, m.p.t. 109- Examples 189 to 224 The compounds set out below were ptepared in the same way as in Example 188, using the appropriate starting materials. (Table Removed) Example 225 (4-Oxo-5-phenyl-3,4-dlhydrothieno[2>3-J]pyrimidin-2-yl)aceUc acid ethyl ester Hydrogen chloride gas was bubbled through a stirred reaction mixture of 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester (4.94g, 0.02mol) in ethyl cyanoacetate (50ml) for 2 hours. A thick suspension formed initially which slowly dissolved on gentle watming. The mixture was allowed to stand at ambient temperatura for 18 hours. Excess hydrogen chloride was removed by bubbling nitrogen through the reaction mixture and most of the excess ethyl cyanoacetate was distilled out at reduced pressure. The solid residue was recrystallised from ethanol to give (4-oxo-5-phenyl-3,4-dihydrothieno[2,3-rf]pyrimidin-2-yl)acetic acid ethyl ester (3.64g), which was used without further purification. Examples 226 to 230 The compounds set out below were prepared in thc same way as in Example 225, using the appropriate starting materials. (Table Removed) Example 231 (4-Chk>ro-5-phenylthieno[2^-d]pyrimidin-2-yl)acetic acid ethyl ester A stirred solution of (4^xo-5^henyl-3,4^hydrothieno[2,3-^Jpyrimidin-2-yl)acetic acid ethyl ester (l.Og, 3.185mmol), phosphoryl chloride (15ml) and N^V-dimethylaniline (4.8ml) was heated under reflux for 6 hours and then left to stand at ambient temperatura for 18 hours. The excess phosphoryl chloride was removed in vacuo to give a dark residue, which was dissolved in dichloromethane (lOOml) and then washed with water (2x50ml) followed by saturated sodium hydrogen carbonate solution (50ml). The organic layer was dried (MgSO4) and the solvent was removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with dichloromethane and 40°-60° petroleum ether (3:1) gave (4-chloro-5-phenylthieno[2,3-rflpyrimidin-2-yl)acetic acid ethyl ester as a pale-yellow solid (0.86g). Examples 232 to 236 The compounds set out bdow were prepared in the same way as in Example 231, using the appropriate starting matedals. (Table Removed) Example 237 {5-Phenyl-(pyridin-2-ylmethyl)amino]thieno[2,3- A stined mixture of (4-chloro-5-phenyltnieno[2,3^flpyrimidin-2-yl)acetic acid ethyl ester (0.36g, l.OSmmol), 2-aminomethylpyridine (0.12nal, 1.19mmol), triethylamine (0,17ml, 1.19nunol) and ethanol (8ml) was heated under reflux for 4 hours. The solution was then cooled to ambient temperature, poured into water (lOOml) and extracted with dichloromethane (3x50ml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with ethyl acetate and 40°-60° petroleum ether (1:2) gave {5-phenyl-4-[(pyridin-2-yhnethyl)amino]thieno[2,3-d]pyrimidin-2-yl} acetic acid ethyl ester as a colourless gum (0.41g). Examples 238 to 249 The compounds set out below were prepared in the same way as in Example 237, using the appropriate starting raaterials. (Table Removed) Example 250 {S-Phenyl-tCpyridin-l-ylmethyDamlnoJthienotZ^^pyrimidin-l-yl^thanoI A stirrcd solution of {5-phcnyl^[^yridin-2-ylmethyl)amino]thieno[2,3- The compounds set out bdow were prepared in the same way as in Example 250, using the appropriate starting materials. (Table Removed) Example 263 2-{5-Phenyl^[(pyridin-2-yImethyl)amino]thieno[2,3-J]pyrimidin-2-yI}malonicacid diethyl ester Sodium hydride (60% dispersion in oii, 64mg, 1.59mmol) was treated with a solution of {5-phenyl-4-[(pyridin-2-ylnM5thyl)amino]thieno[2,3- Examples 264 to 274 The compounds set out below were preparcd in thc same way as in Example 263, using the appropriate starting materials. (Table Removed) Example27S 2"{5-PhenyI-4-[(pyridin-2-j1raediyl)-amino]-thieno[2^-d]pyriinidin-2-yl}-propane-1,3-diol A stirred solution of 2-{5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-^]pyrimidin- 2-yl}malonic acid diethyl este* (0.32g, 0.672mmol) in anhydrous tetrahydrofuran (lOml) was cooled in an ice-bath and trcated, under a nitrogen atmosphere, with diisobutylaluminium hydride (IM solution in hexane, 5.52ml, 5.52mraol) over 15 minutes. The reaction mixture was allowed to warm up and left to ştir at ambient temperature for 3 hours. The resultant mixture was then cooled in an ice-bath and quenched by the slow addition of methanol (5ml) followed by water (lOml). The mixture was then diluted with 2M sodium hydtoxide solution (SOml) and extracted with ethyl acetate (3x50ml). The combined organic extracte were dried (MgSCU) and the solvent removed in vaeuo to give the crude product. Purification by flash chromatography (silica) eluting with 5% methanol in dichloromethane gave 2-{5-phenyl-4-[(pyridin-2-ylnwthyl)amino]thieno[2,3- The compounds set out below were prepared in the same way as in Example 275, using the appropriate starting materials. (Table Removed) Example 287 Ar-Methyl.2-{5-phenrW{p-lţacctoinide In a lOml glass tube were placed {5-phenyl-4-[^>yridin-2-ylmethyl)amino]thieno[2,3-rf]pvrimidm-2-yl} acetic acid ethyl ester (35mg, 0.088mmol) and a saturated solution of methylamine in ethanol (2.0ml). The tube was sealed with a septum and placed in the microwave cavity. Microwave iiradiation of 200W was used, the temperatul» being raraped fix>m room temperature to KK)°C. Once 100°C was reached, the reaction mixture was held at this temperature for 30 minutes. The temperature was then ramped up to 150°C and the reaction mixtura was held at this temperature for a further 30 minutes. The resultant mixture was diluted with water (50ml) and extracted with dichloromethane (3x50ml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give a residue which was purified by flash chromatography (silica) eluting with 5% methanol in dichloromethane to give JV-methyl-2-{5-phenyl-4-[{pyridin-2-ylmethyl)amino]tiîieno[2,3- The compounds set out below were prepaied in the same way as in Example 287, using the appropriate starting materiala. Example 299 2-Chloromethyl-5"phenyl-3H-thieno[2^- A stoed suspension of 2^hto«Mnethyl-5-phenyl-3H-ttiieno[2,3-d]pyrimidin-4-one (1.5g, 5.42mmol) and phosphoryl chloride (23ml) was heated under reflux for 7 hours and then left to stand at ambient tcmperaturc for 18 hours. The excess phosphoryl chloride was removed in vacuo to give a dark residue, which was dissolved in dichloromethane (lOOml) and then washed with water (2xlOOml) followed by saturated sodium hydrogen carbonate solution (lOOml). The organic extract was dried (MgSO*) and the solvent was removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with dichloromethane gave 4-chloro-2-chloromethyl-5-phenylthieno[2,3-d]pyrimidine as a pale-yellow solid (1.42g). Example 301 (2-ChIoromethyl-5-phenyIthieno[2,3-rf]pyrimidin-4-yl)pyridin-2-yIraethylanune A reaction mixture of 4-chloro-2-chloromethyl-5-phenylthieno[2,3-d3pyrimidine (O.SOg, 1.69mmol), 2-aminomethylpyridine (0.17ml, 1.69mmol), triethylamine (0.26ml, 1.86mmol) and propan-2-ol (15ml) was stirred at ambient temperature for 4 days. The solution was then poured into water (150ml) and extracted with ethyl acetate (3x75ml). The combined organic extracts were dricd (MgSO4) and the solvent rcmoved in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with ethyl acetate and 40°-60* petroleum ether (1:4) gave (2-chloromethyl-5-phenylthieno[2,3-rf}pyrirnidin-4-yl)pyridin-2-ylmethylamine as a yellow solid (0.17g), m.p. 97°-99*C. Example 302 (2-Dimethylaminomethyl-5.phenylthieno[2,3^r]pyriinldin-4-yl)pyridin-2- ylmethylamine In a lOml glass tube were placed (2^;hloromethyl-5-phenylthieno[2,3-d]pyrimidin-4-yl)pyridin-2-ylmethylamine (SOmg, 0.136mmol) and a saturated solution of dimethylamine in ethanol (2.0ml). The tube was sealed with a septum and placed in the microwave cavity. Microwave irradiau'on of 200W was used, the temperature being ramped from room temperature Do 150%;. Once 1SO°C was reached, the reaction mixture was held at this temperature for 10 minutes, The resultant mixture was diluted with water (50ml) and extracted with dichloromethane (3x50ml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with 4% triethylamine in ethyl acetate gave (2- The compounds set out below were prepared in the same way as in Example 302, using the appropriate starting materials. Example 303 Compound (2-Morpholin-4-ylmethyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylraethyl-amine 304 (2-Methylaminornethyl-5-phenyl-thieno[2,3-djpvrirnidin-4-yl)-pyridin-2-ylrnethyl-amine Example 305 (2-Methoxymethyl-5-phenylthien[2primidin-yI)pyrIdin-2-yImethyIamine In a lOml glass tube was placed anhydrous methanol (îmi). This was coolcd in an ice-bath and treated with sodium hydride (60% dispersion in oii, 6mg, 0.147mmol). After stirring for about 10 minutes, (2-chlofomethyl-5-phenylthieno[2,3- Examle 306 A suspension of 3H^hk3io[2,3- The compound set out below was prepared in the same way as in Example 306 , using the appropriate starting materials. (Table Removed) Eample 308 6-Bromo-4-chlorothieno[2^- Example309 The compound set out below was prepared in the same way as in Example 308, using the appropriate starting materials. (Table Removed) Example 310 5-Bromo-4-chlorothieno[2,3-rf]pyrlmIdine A stirred solution of 6-bromo-4-chlorothieno[2,3-d]pyrimidine (4.0g, 0.016mol) in anhydrous tetrahydrofuran (lOOml) was cooled in a dry-ice/acetone bath and treated, under a nitrogen atmosphere, with lithium diisopropylamide (1.8M solution in tetrahydrofuran, 9.0ml, 0.016mol) over about 20 minutes. The resultant dark solution was stirred in the cold for l hour and then treated with a mixture of water (5ml) and tetrahydrofuran (20ml) over about 20 minutes. The mixture was then allowed to warm up to about 0°C before being poured into water (250ml) and extracted with dichloromethane (3x lOOml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with dichloromethane gave 5-bromo-4-chlorothieno[2,3-djpyrimidine as a pale brown solid (3.8g). (5-Bron»tWeno[2,3^pyriniidln^yl)pyridln-2-ylmethylamine A stirred mixtura of 5-bromo-4-chlorothieno[2,3-d3pyrimidine (3.8g, 15.2mmol), ethanol (250ml), triethylamine (2.32ml, I6.7mmol) and 2-aminomethylpyridine (1.72ml, 16.7mmol) was heated under reflux for 2.5 hours. The solution was then cooled to ambient temperatura, poured into water (300ml) and extracted with dichloromethane (3xl50ml). The combined organic extracts were dried (MgSO Example312 [5-(l-Methyl-l//-indol-5-yl)thieno[2,3-if]Pyrimldin-4-yl]pyridin-2-ylmethyIanilne Ih a lOml glass tube were placed 5-bromothieno[2,3-d]pyriniidin-4-yl)pyridin-2-ylmethylamine (47mg, 0.146mmol), N-methylindole-5-boronic acid (Slmg, 0.294mmol), polymer-bound triphen^phosphine-Pd(0) (Argonaut PS-PPh3-Pd, 0.13rnmol/g,146mg, 0.0146mmol), sodium carbonate (46mg, 0.440mmol), dimethoxyethane (0.75ml), ethanol (0.75mJ) and water (O.Sml). The tube was sealed with a septum and placed in the microwave cavity. Microwave irradiation of 200W was used, the temperature being ramped frora room temperature to 150°C. Once ISO^C was reached, the reaction mixture was held at this temperature for l hour. The resultant mixture was filtered through Kieselguhr, the filtered solid being washed through with water and dichloromethane. The filtrate was then extracted with dichloromethane (3x50ml) and the organic extracts dried (MgSCU). The solvent was removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with ethyi acecate and 40°-6Q° petroleum ether (2:1) gave [5-(l-methyl-l^-indol-5-y])thieno[2,3- (Table Removed) Ex ample 334 5-Broino-6-inethyI-lH-thieiio[2^- Examle 335 A stirred mixture of 5-bromo^methyl-lH-thieno[2,3-d]pyriinidine-2,4-dione (2.43g, 9.3mmol) and phenylphosphonic dichloride (15ml) was heatcd at a temperature of 150°C for 6 hours in a vessel protected by a calcium chloride drying tube. The reaction mixture was allowed to cool to ambient temperature and pourcd into ice-water (250ml). After stimng for 45 minutes, the resulting mixture was extracted with dichloromethane (SxlOOml). The combined organic extracte were washed with water (lOOml) followed by saturated sodium hydrogen carbonate solution (lOOml) and dried (MgSO*). The solvent was removed in vacuo to give the crude product which was purified by flash chromatography (silica) eluting with dichloromethane giving 2.02g of 5-bromo-2,4-dichlorcH^-methylthieno[2,3-J]pyrimidine as a yellow solid. Example 336 5-Bromo-2-chloro-6-methylthieno[2,3-rf3pyrimidin-4-yl)pyridin-2-ylmethylamuie A stirred mixture of 5-bromo-2,4^chloro-6-methylthieno[2,3-^/lpyrunidine (l.Og, 3.35mmol), ethanol (40ml), 2-aminomethylpyridine (0.40ml, 3.69mmol) and triethylamine (O.SOmI, 3.69mmol) was heated at a temperature of 60°C for l hour. The reaction mixture was then cooled to ambient temperature, diluted with water (lOOml) and extracted with dichloromethane (3x50ml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give a residue. Purification by flash chromatography (silica) eluting with dichloromethane followed by 5% ethyl acetate in dichloromethane gave (5-bromo-2 The compound set out below was prepared in the same way as in Example 336, using the appropriate starting raaterials. Example 338 2-[{5-Bromo-6-methyl-4-[(pyridin-2-yIraethyI)aniino]thieDo[2,3-J]pyrimidin-2-yl}- (2-hydroxyethyI)amino]ethanoI Bi a lOml glass tube were placed 5-bromo-2-chloro-6-methylthieno[2,3-flpyrimidin-4-yl)pyridin-2-yImethylaniine (O.lOg, 0.27ramol) and diethanolamine (O.SOml). The tube was sealed with a septum and placed in the microwave cavity. Microwave irradiation of 200W was used, the temperature being nunped from room temperaturc to 200°C. Once 200°C was reached, the reaction mixturc was held at this temperaturc for 30 minutes. After cooling to ambient temperature, water (50 ml) was added and the mixture extracted with dichloromethane (3xSO ml). The combined organic extracts were dried (MgSCU) and the solvent removed in vacuo to give the crude product which was recrystallised from dichloromethane to give 2-[{5-bromo-6-methyl-4-[(pyridin-2-ylmethyl)amino]thieno [2,3^pyrimidin-2-yl}-(2-hydroxyethyl)amino]ethanol as a white solid (0.71g), m.pt. 152°C. Examples 339 to 341 The compounds set out below were preparcd in the same way as in Example 338, using the appropriate starting materials. (Table Removed) Example 342 2-((2-hydroxyethyl)-{6-methyl-5-phenyl-4-[(pyridin-2-ylmethyI)amino]thieno[2- d]pyrimidin-2-yl}amlno)ethanoI In a lOml glass tube were placed 2-[{5-bromo-6-methyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-d]pyriini(Bn-2-yl}-(2-hydroxyethyl)ainino]ethanol (32mg, 0.073mmol), phenylboronic acid (20mg, 0.166mmol), sodium carbonate (26mg, 0.249mmol), triphenylphosphine (7mg, 0.025mmol), palladium(II)acetate (2mg, O.OOSmmol), dimethoxyethane (0.75ml) and water (0.25ml). The tube was sealed with a septum and placed in the microwave cavity. Microwave irradiation of 200W was used, tbe temperaturc being ramped from room temperature to 150°C. Once 150°C was reached, the reaction mixture was held at this temperature for l nour. The resultant mixture was diluted with water (50ml), extracted into dichloromethanc (3x50ml) and the combined organic extracts were dried (MgSO4). The solvent was removed in vacuo to give the crude product which was purified by flash chromatography (silica) eluting with ethyl acetate followed by 5% methanol in ethyl acetate to give 2-((2-hydroxyethyl)-{6-meM-5-phenyM-[(pvridin-2-ytaielhyl)ainino]thieno[2,3pyrimidin-2-yl}amino)ethanol as a brown gum (7mg). Examples 343 to 353 The compounds set out below were prepared in the same way as in Example 342, using the appropriate starting materials. (Table Removed) 2-{6-Methyl-5-phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2-ylamino} -ethanol (Table Removed Example 355 Bioassays-Kvl.5 Rb* Efflux Assay The pope of a potasaium channcl is permeabie to odwr monovalent cations midi as Rb* and Tl+. Analysis of cellular efflux of potassium channel permeable ions enables potassium channel activity to be monitored directly. Cells stably transfected with cDNA for human Kvl.5 (in pEF6::VA-His-TOPO) were grown in Dulbecco's Modified Eagle media (DMEM) alpha supplemented with 10% Fetal Calf Serum (FCS), 20 ftl/ml penicillin (5000U/ml) streptomycin (5000/ig/ml), 10/d/ml [lOOx] glutamine, and blasticidin (7.5ng/ml). Cells were dispensed into 96 well cellstar TC plates and allowed to grow until a confluent monolayer was visible. On the morning of the assay run, cold media waa aspirated using the TECAN plate wasner, and a 5001 media spike containing 2MCi/ml (37kBq/ml) *Rb* added to each well containing cells using the Shallow-Wcll Matrix Platemate. Plates were placed in a incubator at 37°C for a minimum of 3 hours. Unloaded ^Rb* in the "hoţ" media was aspirated and each well washed 4x250/tl with Earis Balanced Salt Solution (EBSS) which contained SmM KC1, 140mM NaCl, 2mM CaCl2, ImM MgSO4, lOmM HEPES, and SmM glucose, pH 7.4,290-300 mOsm. These cells were then pre-incubated with 50/tl of EBSS +/- test compounds for 10 minutes at room temperature. After the 10 minute incubation, 50/il of modified EBSS which contained 145mM KCI, 2mM CaCl2, ImM MgSO4, lOmM HEPES, SmM glucose, pH 7.4, 290-300 mOsm, was added, and the cells were incubated for a further 10 minutes at room temperature. The high KCI EBSS was used to depolarise cells to a membrane potenţial that would activate Kvl.5 channels. After the final incubation 80fil/100ul of the reaction from each well was transferred to equivalent wells in a Packard "Optiplate" white % well plate and counted in a Packard TopCount liquid scintillation counter by Cerenkov emission. Percentage inhibition 86Rb+ efflux through Kvl.5 was calculated by normalisation to. 2.5mM 4 amino-pyridine control block of Kvl.5. Alternatively cells were loaded with 85Rb+ and quantified by atomic absorption spectroscopy. ÎCso determinations were derived from 10 point concentration response curves n=2 using the (Table Removed) Example 356 Kvl.5 Autopatch Electrophysiology Method The externai bathing solution contained (in mM): 150 NaCl, 10 KC1, 100 Potassium Gluconate, 3 MgCfe, l CaCl2, 10 HEPES, pH 7.4. Patch pipettes were filled with an electrode solution of composition (in mM): 160 KC1,0.5 MgCfc, 10 HEPES, l EGTA, pH 7.4 with KOH. Compounds were dissolved in DMSO (100 %) and made up in the externai bather at a concentration of lyM. AII experimente 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 15ral centrifuge tube and transferred to an incubator (37°C, 5% CO2) for approximately one hour before use. Foilowing 60 min incubation, a tube was taken and centrifuged at 1000 rpm for 4 mins at room temperature. 9.5 ml supernatant was thence discarded, leaving a cell pellet at the bottom of the tube. The pellet was then resuspended using 100 ui of cold (4 °C), filtered (0.22 ujtn), 0.2 % BSA/bathcr solution (0.02g BSA/lOml bather). The bottom of the tube was manually agitated gently until the solution became cloudy with cells. The 100 ui cell resuspension solution was then stored on the bench at 4 °C (using a Peltier-based temperature control device) undi 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. A 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 AutoPatch™. Borosilicate glass patch pipettes (from l.Smm OD, thin-walled filamented, GC150-TF capillary glass, Harvard) were pulled using a DMZ pipette puller (Zeitz Instruments), and were back-filled using the internai pipette solution, being careful that no bubbles remain at the tip or in the body of the pipette. Patch pipettes typically hâd resistances of 2.3-3.5 M&. 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 AutoPatch™. 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 recoidings were made using the AutoPatch™ rig, which incorporated an EPC9 amplifier (HEKA, Germany) under control of Puise 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 18 MQ 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 /K > 500 pA were used for experimente. Cells were continuously perfused with externai solution at a flow rate of 1.8-2 ml/minute. The perfusion chamber hâd a working volume of 80-85fJl and allowed for rapid exchange of drug solutions. Online analysis of the HKV1.5 current during the application of compounds was performed by the AutoPatch™ software. Voltage-step protocols and analysis of data was performed as described for convenţional electrophysiology. Electrophysiology voltage-step protocols and analysis of data was performed as follows. Data was sampled at SkHz, and filtered with a -3 dB bandwidth of 2.5kHz. Cells were held at a voltage of -80mV. Currents were evoked to a voltage step for lOOOms in duraţion at OmV every 5s. 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). (Table Removed) References Herbert, "General principles of the strueture of ion channels", Am. J. Med, 104, 87-98, 1998. Annstrong & Hale, "Voltage-gated ion channels and electrical excitability", Neuron, 20, 371-380,1998. Gutman GA, Chandy KG, Adelman JP, Aiyar J, Bayliss DA, Clapham DE, Covaniubias M, Deşir GV, Furuichi K, Ganetzky B, Gatcia ML, Grissmer S, Jan LY, Karschin A, Kim D, Kuperschmidt S, Kurachi Y, Lazdunski M, Lesage F, Lester HA, McKinnon D, Nichols CG, OTCelly X, Robbins J, Robertaon GA, Rudy B, Sanguinctti M, Seino S, Stuehmer W, Tamioun MM, Vandenberg CA, Wei A, Wulff H, Wyraore RS International Union of Pharmacology. XIX Compendium of voltage-gated ion channels: potassium channels. Pharmacol Rcv. 2003 Dec;55(4):583-6. Shieh et al. "Potassium channels: molecular defecte, diseases, and therapeutic opportuniu'es", Pharmacol Rev, 52(4), 557-594,2000. Ford et al, "Potaasiuin Channels: Gene Family, Therapeutic Relevance, Bfigh-Throughput Screening Technologies and Drag Dificovery", Prog Drug Res, 55,133-168,2002. Marban "Cardiac channelopalthies", Nature, 415,213-218,213-218,2002. Brendel and Peukert 'Blockers of the Kvl.5 Channel for the Treatment of Atrial Arrhythmias', Expert Opinion in Therapeutic Patents, 12 (l 1), 1589-1598 (2002). Wang et al., "Sustained depolarization-induced outward current in human attial myocytes. Evidence for a novei delayed rcctifier KH- current similar to Kvl.5 cloned channel currents", Circ Res, 73,1061-1076,1993. Fedida et al., "Mentity of a novei delayed rectifier current from human heart with a cloned K+ channel current". Circ Res, 73,210-216,1993. Feng et al, "Antisense oligodeoxynucleotides directed against Kvl.S mRNA specifically inhibit ultrarapid delayed rectifier K+ current in cultured adult human atrial myocytes", Circ Res, 80,572-579,1997. Amos et al, "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, Issue 2,347-360,2002. Courtemanche et al., "Ionic targets for drug therapy and atrial fibrillation-induced electrica! remodeling: insights Crom a mathematical model", Cardiovasc Res, 42(2), 477-489,1999. Nattel et al, "Cardiac ultrarapid delayed rectifiers: a novei potassium current family of funcţional similarity and molecular diversity", Cell Physiol Biochem, 9(4-5), 217-226, 1999. Knobloch K, Brendel J, Peukert S, Rosenstein B, Busch AE, Wirth KJ. Electrophysiological and antiarrhythmic effects of the novei I(Kur) channel blockers, S9947 and S20951, on left vs. right pig atrium in vivo in comparison with the I(Kr) blockers dofetilide, azimilide, d,l-sotalol and ibutilide. Naunyn Schmiedebergs Arch Pharmacol. 2002 Nov;366(5):482-7. Wîrth KJ, Paehler T, Rosenstein B, Knobloch K, Maier T, Frenzel J, Brendel J, Busch AE, Bleich M.Atrial effccts of the novei K(+)-channel-blocker AVEX)118 in anesthetized pigs. Cardiovasc Res. Nov 1;60(2):298-306,2003. Colatsky et al., "Channel specificity in antianhythmic drug action. Mechanism of potassium channel block and its role in suppressing and aggravating cardiac anhythmias", Circulation, 82(6), 2235-2242,1990. Feng et al., "Effects of class DI antiairhythmic drugs on transient outward and ultra-rapid delayed rectifier eurrents in human atrial myocytes", J Pharmacol Exp Ther, 281(1), 384-392,1997. Wang et al, "Effects of flecainide, quinidine, and 4-aminopyridinc on transient outward and ultrarapid delayed rectifier currents in human atrial myocytes", J Pharmacol, 272(1), 184-196,1995. Malayev et al., "Mechanism of clofîlium block of the human Kvl.5 delayed rectifier potassium channel", Mol Phomaco, 147(1), 198-205,1995. Godreau et al., "Mechanisms of action of antianhythmic agent bertosamil on hKvl.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 novei anti-airhythniic agent, NIP-142, of cloned human cardiac K+channel Kvl.5 current", Life Sci, 68,2017-2024,2001. Bachmann et al., "Characterization of a novei Kvl.5 channel blocker in Xenopus oocytes, CHO cells, human and rât cardiomyocytes", Naunyn Schmiedebergs Arch Phannacol, 364(5), 472-478,2001. Peufcert S, Brendel J, Pirard B, Bruggemann A, Below P, Kleemann HW, Hemmerle H, Schmidt W. Identification, synthesis, and activity of novei blockers of the voltage-gated potassium channel Kvl.5. J Med Chem. Feb 13;46(4):486-98,2003. Xu & 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. Katada et al, 'Cytotoxic effects of NSL-1406, a new thienopyrimidine derivative, on leukocytes and osteoclasts.' Bioorg. Med. Chem. Lett., 9,797-802,1999. Stewart et al, 'Discovery of inhibitors of cell adhesion molecule expression in human endothelial cells. 1. Selective inhibition of IC AM-1 and E-selectin expression', J. Med. Chem., 44,988-1002,2001. Hozien et al, 'Synthesis and application of some new thienopyrimidine derivatives as antimicrobial agents', Synthetic Communications, 26(20), 3733-3755,1996. Ismail et al., 'Synthesis and antimicrobial activity of some tetramethylenethienopyrimidine derivatives', Farmaco, 50(9), 611-616,1995. Konno et al., 'Synthesis of thienopyrimidine derivatives and their antifungal activities', YakugakuZasshi, 109(7), 464-473,1989. Ram et al., Thienopyrimidines as potential chemotherapeutic agents H", J. Het. Chem., 18(7), 1277-1280,1981. Ram et al., Thienopyrimidines as potential chemotherapeutic agents ', Archiv der Pharmazie, 312(1), 19-25,1979. Shehata et al., 'Synthesis, antitumour and antirHTV-1 testing of certain thienopyrimidine, thienoimidazopyrimidine and thienothiazine derivatives' Med. Chem. Res„ 6(3), 148-163,1996. Moneer et al, 'Reaction of SOamino and 4-hydrazino-5,6-tetramethy]enethienopyiimidine derivatives with azlactones', Egyptian Journal of Phatm. Sci., 34 (4-6), 599-609,1994. Jordis etal., '7,9-Dideaza-9-thiaadenines (4-aminothieno[2,3-d]pyrimidines) as potenţial anticytokinins'VestnikSlovenskegaKemijskegaDrustva, 33(3), 217-38,1986. Noravyan et al., 'Synthesis and anticonvulsive activity of 4-alkyl (or aryl)arnino-6,6-dimethyl-5,6-dihydro-8H-pyrano (or thiopyrano)f3,4-b]thieno[5,4-djpyrimidines' Khimiko-Fannatsevticheskii Zhurnal, 11(9), 38-42,1977. Hosni et al., "Thienopyrimidines E: synthesis of newer thienot2,3-d]pyrimidines and their quatemized derivatives with molluscicidal activity' Acta Poloniae Phannaceutica, 56(1)49-56,1999. Munchof et al., 'Design and SAR of thienopyrimidine and thienopyridine inhibitors of VEGFR-2 kinase activity'. Bioorganic & Medicinal Chemistry Letters, 14(1), 21-24, 2004 We Claim: 1. A thienopyrimidine derivatives of formula (I) (Formula Removed) wherein Rl is aryl, heteroaryl or cycloalkyl; R2 is H, alkyl, nitro, CO2R7, CONR4R5 or halo; R3 is H, NR4R5, NHC(O)R8, halo, trifluoromethyl, alkyl, nitrite 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, alkenyl cycloalkyl, an unsubstituted alkyl or an alkyl substituted by halogen, cyano, nitro, NR9R10, alkoxy, unsubstituted aryl, unsubstituted heteroaryl, C(O)NR9R10, NHC(O)R8, or SO2NR9R10; or pharmaceutically acceptable salts thereof; with the proviso that when Y is phenyl, phenyl monosubstituted by C1 or methoxy, furanyl, tetrahydrofurayl, pyrimidinyl, pyrrolidinyl or 1,3- benzodioxolyl, then Rl is not phenyl, phenyl monosubstituted by halogen or phenyl substituted by methyl; and wherein the compound is not: N-Butyl-5-phenylthieno[2,3-d]pyrimidin-4-amine; 5-Phenyl-N-(pyridin-2-ylmethyl)thieno[2,3-d]pyrimidin-4-amine; 5-(4-Chlorophenyl)-N-[3-(lH-imidazol-l-yl)propyl]thieno[2,3-d]pyrimidin-4- amine; 5-(4-Chlorophenyl)-N-(pyridin-2-ylmethyl)thieno[2,3-d]pyrimidin-4-amine; 5-(4-Chlorophenyl)-N-(2-cyclohex-l-en-l-ylethyl)thieno[2,3-d]pyrimidin-4- amine; 5-(4-Chlorophenyl)-N-(pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-4- amine; 5-(4-Chlorophenyl)-N-(2-flirylmethyl)thieno[2,3-d]pyrimidin-4-amine; 5-(4-Fluorophenyl)-N-(pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-4-amine; N-Allyl-5-phenylthieno[2,3-d]pyrimidin-4-amine; 5-(4-Methylphenyl)-N-(2-thien-2-ylethyl)thieno[2,3-d]pyrimidin-4-amine; N-(2-Furylmethyl)-5-phenylthieno[2,3-d]pyrimidin-4-amine; 5-(4-Chlorophenyl)-N-(2-thien-2-ylethyl)thieno[2,3-d]pyrimidin-4-amine; 5-(4-Fluorophenyl)-N-(2-thien-2-ylethyl)thieno[2,3-d]pyrimidin-4-amine; N-Allyl-5-(4-chlorophenyl)thieno[2,3-d]pyrimidin-4-amine; 5-(4-Chlorophenyl)-N-(tetrahydrofuran-2-ylmethyl)thieno[2,3-d]pyrimidin-4- amine; 5-Phenyl-N-(tetrahydrofuran-2-ylmethyl)thieno[2,3-d]pyrimidin-4-amine; 5-(4-Bromophenyl)-N-(pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-4-amine; N-[3-(lH-Imidazol-l-yl)propyl]-5-phenylthieno[2,3-d]pyrimidin-4-amine; l-(2-{[5-(4-Methylphenyl)thieno[2,3-d]pyrimidin-4-yl]amino}ethyl)imidazolidin- 2-one; N-(2-Furylmethyl)-5-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-amine;or N-ethyl-2-methyl-5-(thiophen-2-yl)thieno[2,3-d]pyrimidine-4-amine. 2. A compound as claimed in claim 1 wherein Rl 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 Rl 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 heteroaryl. 4. A compound as claimed in any one of claims 1 to 3 wherein Y is furanyl, thienyl or pyridyl. 5. A compound as claimed in any one of claims 1 to 4 wherein Y is optionally substituted furan-2-yl or optionally substituted pyridin-2-yl. 6. A compound as claimed in claim 1 which is: 2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2-yl}-propane-l,3-diol; 2-{5-(4-Fluorophenyl)-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2-ylamino} -ethanol; Pyridin-2-ylmethyl-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-yl)-amine; 2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2-ylamino}-ethanol; 2-{5-Phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-rf]pyrimidin-2-yl}ethanol; 2-((2-Hydroxy-ethyl)-{5-phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2-yl}-amino)-ethanol; 2-Methyl-N-(2-pyridyl)methyl-5-phenylthieno[2,3-d]pyrimidin-4-ylamine; 2-{4-[(Furan-2-ylmethyl)-amino]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl}-ethanol; [2-(2-Methoxy-ethoxy)-5-phenyl-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2-ylmethyl-amine; (2-Methoxy-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine; 5-(4-Fluorophenyl)-N2-(2-methoxy-ethyl)-N4-pyridin-2-ylmethyl-thieno[2,3-d]pyrimidine-2,4-diamine; [5-(4-Dimethylamino-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2-ylmethyl-amine; 5-(4-Fluorophenyl)-N2,N2-dimethyl-N4-pyridin-2-ylmethyl-thieno[2,3-d]pyrimidine-2,4-diamine; Pyridin-2-ylmethyl-[5-(4-trifluoromethyl-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-amine; [5-(lH-Indol-6-yl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2-ylmethyl-amine; (5-Benzo[l,3]dioxol-5-yl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine; 2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2-ylamino}- propane-l,3-diol; 3 - {5 -Phenyl-4- [(pyridin-2-ylmethyl)-amino] -thieno [2,3 -d]pyrimidin-2-ylamino}- propane-l,2-diol; N-Methyl-2-{5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-d]pyrimidin-2- yl}acetamide; or 6-Methyl-N-[(6-methylpyridin-2-yl)methyl]-5-phenylthieno[2,3-d]pyrimidin-4- amine; and pharmaceutically acceptable salts thereof. 7. A process for preparing a compound as claimed in any one of claims 1 to 6 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 (Formula Removed) (ii) reacting a compound of formula X by displacement of the 2-chloro substituent with a suitable nucleophilic species; or (Formula Removed) (iii) reacting a compound of formula XVII with an aryl or heteroaryl boronic acid, optionally in the presence of a palladium catalyst, and optionally at elevated temperature or with microwave irradiation. (Formula Removed) 8. A pharmaceutical composition comprising at least one compound and optionally one or more excipients, diluents and/or carriers, wherein said compound has the formula- (Formula Removed) Wherein R1 is aryl, heteroaryl or cycloalkyl; R2 is H, alkyl, nitro, CO2R7, CONR4R5 or halo; R3 is H, NR4R5, NHC(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,Sor 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, alkenyl, cycloalkyl, an unsubstituted alkyl or an alkyl substituted by halogen, cyano, nitro, NR9R10, alkoxy, unsubstituted aryl, unsubstituted heteroaryl, C(O)NR9R10, NHC(O)R8, or SO2NR9R10; or pharmaceutically acceptable salts thereof; with the proviso that when Y is phenyl, phenyl monosubstituted by C1 or methoxy, furanyl, tetrahydrofurayl, pyrimidinyl, pyrrolidinyl or 1,3-benzodioxolyl, then R1 is not phenyl, phenyl monosubstituted by halogen or phenyl substituted by methyl. 9. A pharmaceutical composition as claimed in claim 8 wherein said compound is a compound as claimed in any one of claims 1 to 6. 10. A compound, or a pharmaceutical composition comprising said compound for use in medicine, wherein said compound has the formula: (Formula Removed) Wherein Rl is aryl, heteroaryl orcycloalkyl R2 is H, alkyl, nitro, CO2R7, CONR4R5 or halo; R3 is H, NR4R5, NHC(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, Sor NR6; R6 is H or alkyl; R7 is hydrogen, methyl or ethyl; R8 is methyl or ethyl; L is (CHa)n, where n is 1,2 or 3; and Y is aryl, a heterocyclic group, alkenyl, cycloalkyl, an unsubstituted alkyl or an alkyl substituted by halogen, cyano, nitro, NR9R10, alkoxy, unsubstituted aryl, unsubstituted heteroaryl, C(O)NR9R10, NHC(O)R8, or SO2NR9R10; or pharmaceutically acceptable salts thereof; with the proviso that when Y is phenyl, phenyl monosubstituted by C1 or methoxy, furanyl, tetrahydrofurayl, pyrimidinyl, pyrrolidinyl or 1,3-benzodioxolyl, then R1 is not phenyl, phenyl monosubstituted by halogen or phenyl substituted by methyl. 11. A compound or pharmaceutical composition as claimed in claim 10, wherein said compound is a compound as claimed in any one of claims 1 to 6. 12. A compound as claimed in any of the preceding claims as and when used for the treatment of arrhythmia. |
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5815-DELNP-2005-Claims-(29-12-2011).pdf
5815-DELNP-2005-Correspondence-Others-(29-12-2011).pdf
5815-delnp-2005-correspondence-others.pdf
5815-delnp-2005-description (complete).pdf
5815-DELNP-2005-Form-1-(29-12-2011).pdf
5815-DELNP-2005-Form-13-(29-12-2011).pdf
5815-DELNP-2005-Form-2-(29-12-2011).pdf
5815-DELNP-2005-Petition-137-(29-12-2011).pdf
| Patent Number | 256025 | ||||||||||||||||||||||||
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| Indian Patent Application Number | 5815/DELNP/2005 | ||||||||||||||||||||||||
| PG Journal Number | 17/2013 | ||||||||||||||||||||||||
| Publication Date | 26-Apr-2013 | ||||||||||||||||||||||||
| Grant Date | 22-Apr-2013 | ||||||||||||||||||||||||
| Date of Filing | 13-Dec-2005 | ||||||||||||||||||||||||
| Name of Patentee | XENTION DISCOVERY LIMITED | ||||||||||||||||||||||||
| Applicant Address | PAMPISFORD PARK, LONDON ROAD, PAMPISFORD CAMBRIDGE CB2 4EF, UNITED KINGDOM. | ||||||||||||||||||||||||
Inventors:
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| PCT International Classification Number | C07D 495/04 | ||||||||||||||||||||||||
| PCT International Application Number | PCT/GB2004/002454 | ||||||||||||||||||||||||
| PCT International Filing date | 2004-06-10 | ||||||||||||||||||||||||
PCT Conventions:
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