0001 This invention relates to certain substituted thiazolidinedione derivatives, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine. 0002 European Patent Applications, Publication Numbers 0008203, 0139421, 0155845, 0177353, 0193256, 0207581 and 0208420 relate to thiazolidinedione derivatives which are disclosed as having hypoglycaemic and hypolipidaemic activity. Chem. Pharm. Bull 30 (10) 3580-3600 also relates to certain thiazolidinedione derivatives having hypoglycaemic and hypolipidaemic activities. 0003 It has now surprisingly been discovered that certain novel substituted-thiazolidinedione derivatives show improved blood-glucose lowering activity and are therefore of potential use in the treatment and/or prophylaxis of hyperglycaemia and are of particular use in the treatment of Type II diabetes. These compounds are also indicated to be of potential use for the treatment and/or prophylaxis of other diseases including hyperlipidaemia and hypertension. 0004 They are also indicated to be of use in the treatment and/or prophylaxis of cardiovascular disease, especially atherosclerosis. In addition these compounds are considered to be useful for treating certain eating disorders, in particular the regulation of appetite and food intake in subjects suffering from disorders associated with under-eating ,such as anorexia nervosa, and disorders associated with over-eating, such as obesity and anorexia bulimia. 0005 Accordingly, the present invention provides a compound of formula (I): 2

0006 or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein: 0007 A1 represents a substituted or unsubstituted aromatic heterocyclyl group; 0008 R1 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group; 0009 R2 and R3 each represent hydrogen, or R2 and R3 together represent a bond; 0010 A2 represents a benzene ring having in total up to five substituents; and 0011 n represents an integer in the range of from 2 to 6. 0012 Suitable aromatic heterocyclyl groups include substituted or unsubstituted, single or fused ring aromatic heterocyclyl groups comprising up to 4 hetero atoms in each ring selected from oxygen, sulphur or nitrogen. 0013 Favoured aromatic heterocyclyl groups include substituted or unsubstituted single ring aromatic heterocyclyl groups having 4 to 7 ring atoms, preferably 5 or 6 ring atoms. 0014 In particular, the aromatic heterocyclyl group comprises 1, 2 or 3 heteroatoms, especially 1 or 2, selected from oxygen, sulphur or nitrogen. 0015 Suitable values for A1 when it represents a 5-membered aromatic heterocyclyl group include thiazolyl and oxazolyl, especially oxazolyl. 0016 Suitable values for A1 when it represents a 6-membered aromatic heterocyclyl group include pyridyl or pyrimidinyl. 0017 Suitably R2 and R3 each represent hydrogen. 0018 Preferably, A1 represents a moiety of formula (a), (b) or (c): 3

0019 wherein: R4 and R5 each independently represents a hydrogen atom, an alkyl group or a substituted or unsubstituted aryl group or when R4 and R5 are each attached to adjacent carbon atoms, then R4 and R5 together with the carbon atoms to which they are attached form a benzene ring wherein each carbon atom represented by R4 and R5 together may be substituted or unsubstituted; and in the moiety of formula (a) 0020 x represents oxygen or sulphur. 0021 Aptly, A1 represents a moiety of the abovedefined formula (a). 0022 Aptly, A1 represents a moiety of the abovedefined formula (b). 0023 Aptly, A1 represents a moiety of the abovedefined formula (c) 0024 In one favoured aspect R4 and R5 together represent a moiety of formula (d): 4

0025 wherein R6 and R7 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy. 0026 Suitably, R6 and R7 each independently represent hydrogen, halogen, alkyl or alkoxy. 0027 Favourably, R6 represents hydrogen. Favourably, R7represents hydrogen. 0028 Preferably, R6 and R7 both represent hydrogen. 0029 In a further favoured aspect R4 and R5 each independently represent hydrogen, alkyl or a substituted or unsubstituted phenyl group and more favourably, R4 and R5 each independently represent hydrogen, alkyl or phenyl. 0030 Preferably, for the moiety of formula (a), R4 and R5 together represent the moiety of formula (d). 0031 Preferably, for the moieties of formula (b) or (c), R4 and R5 both represent hydrogen. 0032 It will be appreciated that the five substituents of A2 include three optional substituents. Suitable optional substituents for the moiety A2 include halogen, substituted or unsubstituted alkyl or alkoxy. 0033 Favourably, A2 represents a moiety of formula (e): 5

0034 wherein R8 and R9 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy. 0035 Suitably, R8 and R9 each independently represent hydrogen, halogen, alkyl or alkoxy. Preferably, R8 and R9 each represent hydrogen. 0036 Favourably, X represents oxygen. Favourably, x represents sulphur. 0037 In one preferred aspect the present invention provides a class of compounds, which fall wholly within the scope of formula (I), of formula (II): 6

0038 or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, wherein A1, R1, R2, R3, and n are as defined in relation to formula (I) and R8 and R9 are as defined in relation to formula (e). 0039 Suitably, n represents an integer 2, 3 or 4, notably 2 or 3 and especially 2. 0040 Suitably, R1 represents hydrogen, alkyl, acyl, especially acetyl, or benzyl. 0041 When R1 represents an alkyl group, examples of such alkyl groups include methyl and isopropyl. Preferably, R1 represents a methyl group. 0042 As indicated above a compound of formula (I) may exist in one of several tautomeric forms, all of which are encompassed by the present invention. It will be appreciated that the present invention encompasses all of the isomeric forms of the compounds of formula (I) and the pharmaceutically acceptable salts thereof, including any stereoisomeric forms thereof, whether as individual isomers or as mixtures of isomers. 0043 Suitable substituents for any heterocyclyl group include up to 4 substituents selected from the group consisting of: alkyl, alkoxy, aryl and halogen or any two substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, may form an aryl group, preferably a benzene ring, and wherein the carbon atoms of the aryl group represented by the said two substituents may themselves be substituted or unsubstituted. 0044 When used herein the term aryl includes phenyl and naphthyl optionally substituted with up to five, preferably up to three, groups selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups. 0045 When used herein the term halogen refers to fluorine, chlorine, bromine and iodine; preferably chlorine. 0046 When used herein the terms alkyl and alkoxy relate to groups having straight or branched carbon chains, containing up to 12 carbon atoms. 0047 When used herein the term acyl includes alkylcarbonyl groups. 0048 Suitable alkyl groups are C1-12 alkyl groups, especially C1-6 alkyl groups e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl groups. 0049 Suitable substituents for any alkyl group include those indicated above in relation to the term aryl. 0050 Suitable pharmaceutically acceptable salts include salts of the thiazolidinedione moiety, and, where appropriate, salts of carboxy groups. 0051 Suitable pharmaceutically acceptable salts of the thiazolidinedione moiety include metal salts especially alkali metal salts such as the lithium, sodium and potassium salts. 0052 Suitable pharmaceutically acceptable salts of carboxy groups include metal salts, such as for example aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or (2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-P-phenethylamine, dehydroabietylamine, N,N-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine or quinoline. 0053 Suitable pharmaceutically acceptable solvates include hydrates. 0054 In a further aspect the present invention also provides a process for the preparation of a compound of formula (I), or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, which process comprises reacting a compound of formula (III): 7

0055 wherein R2, R3 and A2 are as defined in relation to formula (I), and Ra is a moiety convertible to a moiety of formula (f): 8

0056 wherein R1, A1, and n are as defined in relation to formula (I), with an appropriate reagent capable of converting Ra to the said moiety (f) and thereafter, if required, carrying out one or more of the following optional steps: 0057 (i) converting a compound of formula (I) to a further compound of formula (I); 0058 (ii) preparing a pharmaceutically acceptable salt of the compound of formula (I) and/or a pharmaceutically acceptable solvate thereof. 0059 Suitably, Ra represents R1HN(CH2)nO-wherein R1 and n are as defined in relation to formula (I). 0060 Suitably, when Ra is R1HN(CH2)nO, an appropriate reagent capable of converting Ra to a moiety (f) is a compound of formula (IV):

AlRx(IV)

0061 wherein A1 is as defined in relation to formula (I) and Rx represents a leaving group. 0062 A suitable leaving group Rx includes a halogen atom, preferably a chlorine or bromine atom, or a thioalkyl group for example a thiomethyl group. 0063 The reaction between the compound of formula (III) and the appropriate reagent may be carried out under conditions suitable to the particular compound of formula (III) and the reagent chosen; thus for example the abovementioned reaction between a compound of formula (III) wherein Ra represents R1HN(CH2)nO and the compound of formula (IV), may be carried out in any suitable solvent, for example tetrahydrofuran, at a temperature in the range of between 0 and 60 C. 0064 A compound of formula (III) may be prepared from a compound of formula (V): 9

0065 wherein A2 is as defined in relation to the compound of formula (I) and Rb is a moiety Ra, or a moiety convertible to a moiety Ra; by reaction of the compound of formula (V) with 2,4-thiazolidinedione; and thereafter if required carrying out one or more of the following optional steps: 0066 (i) reducing a compound of formula (III) wherein R2 and R3 together represent a bond, into a compound of formula (III) wherein R2 and R3 each represent hydrogen; 0067 (ii) converting a moiety Rb to a moiety Ra. 0068 The reaction between the compound of formula (V) and 2,4-thiazolidinedione will of course be carried out under conditions suitable to the nature of the compound is of formula (V), in general the reaction being carried out in a solvent such as toluene, suitably at an elevated temperature such as the reflux temperature of the solvent and preferably in the presence of a suitable catalyst such as piperidinium acetate or benzoate. Favourably, in the reaction between the compound of formula (V) and 2,4-thiazolidinedione, the water produced in the reaction is removed from the reaction mixture, for example by means of a Dean and Stark apparatus. 0069 When Ra represents R1HN(CH2)nO, a suitable value for Rb is a hydroxyl group. 0070 The moiety Rb may be converted to the moiety Ra by any suitable means, for example when Rb represents a hydroxyl group and Ra represents R1HN(CH2)nO the appropriate conversion may be carried out by coupling a compound of formula (VA): 10

0071 wherein R2, R3 and A2 are as defined in relation to formula (I) and RZ is hydrogen or a nitrogen protecting group, with a compound of formula (VI):

R1NRX(CH2)nOH(VI)

0072 wherein R1 and n are as defined in relation to formula (I) and Rx is hydrogen or a nitrogen protecting group, in the presence of a suitable coupling agent; and thereafter, if required, carrying out one or more of the following optional steps: 0073 (i) reducing a compound of formula (III) wherein R2 and R3 together represent a bond, to a compound of formula (III) wherein R2 and R3 each represent hydrogen; 0074 (ii) removing any nitrogen protecting group. 0075 A suitable coupling agent for the coupling reaction between the compound of formula (VA) and (VI) is provided by diethylazodicarboxylate and triphenylphosphine. The coupling reaction may be carried out in any suitable solvent at a low to medium temperature, for example in tetrahydrofuran at a temperature in the range of between 0 and 60 C. 0076 One example of the preparation of a compound of formula (VA) is that wherein a compound falling within formula 0077 (v) of particular formula (VII): 11

0078 wherein A2 is as defined in relation to formula (I), and R11 represents a hydroxyl group or a protected hydroxyl group, is reacted with 2,4-thiazolidinedione; and thereafter if required removing any protecting group. 0079 Preferably, R11 represents a benzyloxy group. 0080 Suitable conditions for the reaction between a compound of formula (VII) and 2,4-thiazolidinedione are those defined above in relation to the reaction between the compounds of formula (V) and 2,4-thiazolidinedione. 0081 The compounds of formula (IV), (VI) and (VII) are either known compounds or are prepared using methods analogous to those used to prepare known compounds. 0082 Suitable protecting groups in any of the abovementioned reactions are those used conventionally in the art. Thus, for example, a suitable nitrogen protecting group is a benzyl group or a benzyloxycarbonyl group and a suitable hydroxyl protecting group is a benzyl group. 0083 The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected. Thus for example when 0084 R11 represents a benzyloxy group such group may be prepared by treatment of the appropriate compound of formula (VII), wherein R11 is a hydroxyl group with a benzyl halide, such as benzyl bromide, and thereafter when required the benzyl group may be conveniently removed using a mild ether cleavage reagent such as trimethylsilyliodide. 0085 A compound of formula (I), or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may also be prepared by reacting a compound of formula (VIII): 12

0086 wherein R1, A1, A2, and n are as defined in relation to formula (I) with 2,4-thiazolidinedione; and thereafter if required carrying out one or more of the following optional steps: 0087 (i) converting a compound of formula (I) into a further compound of formula (I); 0088 (ii) preparing a pharmaceutically acceptable salt of a compound of formula (I) and/or a pharmaceutically acceptable solvate thereof. 0089 The reaction between a compound of formula (VIII) and 2,4-thiazolidinedione may suitably be carried out under analogous conditions to those used in the reaction between a compound of formula (V) and 2,4-thiazolidinedione. 0090 A compound of formula (VIII) may be prepared by reacting a compound of formula (IX): 13

0091 wherein A2 is as defined in relation to formula (I) and Ra is as defined in relation to formula (III), with an appropriate reagent capable of converting Ra to the above defined moiety (f). 0092 Suitable values for Ra include those described above in relation to the compound of formula (III). Thus Ra may represent R1HN(CH2)nO, as defined above, and hence the appropriate compound of formula (IX) may be reacted with a reagent of the abovedefined formula (IV) to provide the required compound of formula (VIII). 0093 Suitable reaction conditions for the reaction of the compound of formula (IX) and the appropriate reagent may include those described above in relation to the preparation of compound (III) with the said appropriate reagent. 0094 Preferably, for the compound of formula (IX), Ra represents a leaving group, especially a fluorine atom. When Ra represents a leaving group, preferably a fluorine atom, a particularly appropriate reagent is a compound of formula (X): 14

0095 wherein R1, A1, and n are as defined in relation to formula (I). 0096 The reaction between the compounds of formulae (IX) and (X) may be carried out under any suitable conditions, for example in a solvent such as dimethylformamide or dimethylsulphoxide at an elevated temperature for example in the range of between 100 to 150 C., suitably in the presence of a base such as sodium hydride or potassium carbonate. 0097 In the compound of formula (IX) Ra may also represent a hydroxyl group. 0098 When Ra, in the compound of formula (IX), represents a hydroxyl group a particularly appropriate reagent is a compound of the abovedefined formula (X) or a compound of formula (XA): 15

0099 wherein A1, R1 and n are as defined in relation to formula (X) and RY represents a tosylate or mesylate group. 0100 The reaction between the compound of formula (IX) wherein Ra is a hydroxyl group and the reagent of the abovedefined formula (X) may suitably be carried out in an aprotic solvent, such as tetrahydrofuran, at low to medium temperature, for example at ambient temperature, and preferably in the presence of a coupling agent such as that provided by triphenylphosphine and diethylazodicarboxylate. 0101 The reaction between the compound of formula (IX), wherein Ra is a hydroxyl group, and the reagent of the abovedefined formula (XA) may be carried out in an aprotic solvent, such as dimethylformamide, at a low to elevated temperature, for example in the range of from 50 C. to 120 C. and preferably in the presence of a base, such as sodium hydride. 0102 The compound of formula (XA) may be prepared from the corresponding compound of formula (X) by reaction with either a tosyl halide or a mesyl halide in a solvent such as pyridine. 0103 The compounds of formula (IX) are known compounds or compounds prepared by methods analogous to those used to prepare known compounds, for example 4-fluorobenzaldehyde and 4-hydroxybenzaldehyde are known commercially available compounds. 0104 The reagent of formula (X) may be prepared by reacting a compound of the hereinabove defined formula (IV), with a compound of the hereinbefore defined formula (VI) and thereafter if required removing any nitrogen protecting group using the appropriate conventional conditions. 0105 The reaction between the compounds of formula (IV) and (VI) may be carried out under any suitable conditions, such as in solvent, for example in an aprotic solvent such as tetrahydrofuran, at a low to medium temperature, for example a temperature in the range of from 0 to 60 C. 0106 Favourably when R1 represents hydrogen the reaction is carried out using the compound of formula (VI) as a solvent at a low to elevated temperature, suitably an elevated temperature such as in the range of between 100 and 170 C. 0107 The abovementioned conversion of a compound of formula (I) into a further compound of formula (I) includes the following conversions: 0108 (a) reducing a compound of formula (I) wherein R2 and R3 together represent a bond, to a compound of formula (I) wherein R2 and R3 each represent hydrogen; and 0109 (b) converting one group R1 into another group R1. 0110 The conversion of a compound of formula (I) to a further compound of formula (I) may be carried out by using any appropriate conventional procedure. 0111 A suitable reduction method for the abovementioned conversion (a) includes catalytic reduction or the use of a metal/solvent reducing system. 0112 Suitable catalysts for use in the catalytic reduction are palladium on carbon catalysts, preferably a 10% palladium on charcoal catalyst; the reduction being carried out in a solvent, for example dioxan, suitably at ambient temperature. 0113 Suitable metal/solvent reducing systems include magnesium in methanol. 0114 The abovementioned reduction of a compound of formula (III) wherein R2 and R3 together represent a bond to a compound of formula (III) wherein R2 and R3 each represent hydrogen, may be carried out under analogous conditions to those referred to above in conversion (a) of the compound of formula (I). 0115 In the abovementioned conversion (b), suitable conversions of one group R1 into another group R1 includes converting a group R1 which represents hydrogen into a group R1 which represents an acyl group. 0116 The conversion of a compound of formula (I) wherein R1 represents hydrogen into a compound of formula (I) wherein R1 represents acyl may be carried out using any appropriate conventional acylation procedure, such as by treating an appropriately protected compound of formula (I) with an acylating agent. For example acetic anhydride may be used to prepare the compound of formula (I) wherein R1 is acetyl. 0117 It will be appreciated that in the abovementioned conversions (a) and (b), any reactive group in the compound of formula (I) would be protected, according to conventional chemical practice, where necessary. 0118 Where appropriate the isomeric forms of the compounds of formula (I) and the pharmaceutically acceptable salts thereof may be prepared as individual isomers using conventional chemical procedures. 0119 As mentioned above the compounds of the invention are indicated as having useful therapeutic properties: 0120 The present invention accordingly provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance. 0121 Thus the present invention provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of hyperglycaemia, hyperlipidaemia and hypertension. 0122 A compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. 0123 Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of the general formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor. 0124 As used herein the term pharmaceutically acceptable embraces compounds, compositions and ingredients for both human and veterinary use: for example the term pharmaceutically acceptable salt embraces a veterinarily acceptable salt. 0125 The composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use. 0126 Usually the pharmaceutical compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection and percutaneous absorption are also envisaged. 0127 Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules. Other fixed unit dosage forms, such as powders presented in sachets, may also be used. 0128 In accordance with conventional pharmaceutical practice the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant. 0129 Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate, sodium lauryl sulphate or sucrose. 0130 Most suitably the composition will be formulated in unit dose form. Such unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 0.1 to 500 mg, and more especially 0.1 to 250 mg. 0131 The present invention further provides a method for the treatment and/or prophylaxis of hyperglycaemia or hyperlipidaemia in a human or non-human mammal which comprises administering an effective, non-toxic, amount of a compound of the general formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof to a hyperglycaemic human or non-human mammal in need thereof. 0132 The present invention further provides a method for the treatment of cardiovascular disease, especially atherosclerosis, in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof. 0133 The present invention also provides a method for the treatment of certain eating disorders, in particular the regulation of appetite and food intake in disorders associated with under-eating, such as anorexia nervosa, and disorders associated with over-eating, such as obesity and anorexia bulimia, in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof. 0134 Conveniently, the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention. 0135 In the above mentioned treatments the compound of the general formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may be taken in doses, such as those described above, one to six times a day in a manner such that the total daily dose for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500 mg. 0136 In the treatment and/or prophylaxis of hyperglycaemic non-human mammals, especially dogs, the active ingredient may be adminstered by mouth, usually once or twice a day and in an amount in the range of from about 0.025 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg. Similar dosage regimens are suitable for the treatment and/or prophylaxis of hyperlipidaemia in non-human mammals. 0137 The following Procedures and Examples illustrate the invention but do not limit it in any way. 0138 Preparation 1 0139 4-2-(N-Methyl-N-(2-benzothiazolyl)amino)ethoxy-benzaldehyde 16

0140 A mixture of 4-fluorobenzaldehyde (1.5 g) and 2-N-methyl-N-(2-benzothiazolyl)aminoethanol (2.4 g) in dimethyl sulphoxide (50 ml) containing anhydrous potassium carbonate (2 g) was stirred at 100 C. for 24 hours. The mixture was cooled to room temperature and added to water (300 ml). The aqueous solution was extracted with diethyl ether (2300 ml). The organic extracts were washed with brine (1300 ml), dried (MgSO4), filtered and evaporated to dryness. The title compound was obtained as a waxy solid following chromatography on silica-gel in 1% methanol in dichloromethane. 0141 1H NMR (CDCl3) 0142 3.2 (3H, s); 3.8 (2H, t); 4.2 (2H, t); 6.8-7.8 (8H, complex); 9.8 (1H, s). 0143 Preparation 2 0144 2- N-Methyl-N-(2-benzothiazolyl)aminoethanol 17

0145 A mixture of 2-chlorobenzothiazole (8.5 g) and 2-methylaminoethanol (20ml) was heated at 120 C. under pressure in a sealed, glass lined, stainless steel reaction vessel for 18 hours. After cooling, the oil was added to water (100 ml), extracted with dichloromethane (2100 ml), the organic extracts were dried (MgSO4), filtered and evaporated to dryness. Chromatography of the residual oil on silica-gel in 2% methanol in dichloromethane gave the title compound which was used in Preparation 1 without further purification. 0146 1H NMR (CDCl3) 0147 3.15 (3H, s); 3.4-4.0 (4H, m); 4.7 (1H, broad s, exchanges with D2O); 6.8-7.6 (4H, complex). 0148 Preparation 3 0149 4-2-(N-Methyl-N-(2-benzoxazolyl)amino)ethoxy-benzaldehyde 18

0150 To a solution of 2-N-methyl-N-(2-benzoxazolyl) aminoethanol (9.6 g), triphenylphosphine (13.1 g) and 4-hydroxybenzaldehyde (6.1 g) in dry tetrahydrofuran (150 ml) was added dropwise a solution of diethyl azodicarboxylate (9.0 g) in dry tetrahydrofuran (30 ml), under a blanket of nitrogen with stirring at room temperature. The solution was stirred overnight at room temperature following which the solvent was removed under reduced pressure. The residue was dissolved in diethyl ether (300 ml), filtered and the ether solution was washed with dilute sodium hydroxide solution (200 ml), saturated brine (200 ml), dried (MgSO4), filtered and the solvent evaporated. The title compound (mp 97-98 C.) was obtained after chromatography on silica-gel, eluting with dichloromethane. 0151 1H NMR (CDCl3) 0152 3.30 (3H, s); 3.85 (2H, t); 4.30 (2H, t) 6.80-7.85 (8H, complex); 9.85 (1H, s). 0153 Preparation 4 0154 2-N-Methyl-N-(2-benzoxazolyl)aminoethanol 19

0155 A solution of 2-chlorobenzoxazole (15.4 g) in dry tetrahydrofuran (50 ml) was added dropwise to an ice cooled solution of 2-methylaminoethanol (15.0 g) in dry tetrahydrofuran (10 ml) with stirring and protection from atmospheric moisture. The mixture was stirred at 0 C. for 1 hour, allowed to warm to room temperature and stirred for a further 2 hours. The solvent was removed under reduced pressure, the product was dissolved in ethyl acetate (200 ml) and washed with brine (2150 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated. Chromatography ok the residue on silica-gel in dichloromethane gave the title compound (mp 62-3 C.) which was used in Preparation 3 without further purification. 0156 1H NMR (CDCl3) 0157 3.12 (3H S); 3.4-4.0 (4H, m); 4.7 (1H, s, exchanges with D20); 6.8-7.4 (4H, complex). 0158 Preparation 5 0159 4-2-(N-Methyl-N-(2-pyrimidinyl)amino)ethoxy-benzaldehyde 20

0160 A mixture of 4-fluorobenzaldehyde (12 ml) and 2-N-methyl-N-(2-pyrimidinyl)aminoethanol (10.05 g) in dry dimethyl sulphoxide (50 ml) containing anhydrous potassium carbonate (15 g) was stirred at 120 C. for 6 hours. The mixture was cooled to room temperature and added to water (200 ml). The aqueous solution was extracted with ethyl acetate (2300 ml), the organic extracts washed with brine, dried (MgSO4) and evaporated. The title compound was obtained as an oil following chromatography on silica-gel in 2% methanol in dichloromethane. 0161 1H NMR (CDCl3) 0162 3.3 (3H, s); 3.8-4.4 (4H, complex); 6.5 (1H, t); 7.0 (2H, d); 7.8 (2H, d); 8.3 (2H, d); 9.9 (1H, s). 0163 Preparation 6 0164 2-N-Methyl-N-(2-pyrimidinyl)aminoethanol 21

0165 A mixture of 2-chloropyrimidine (10 g) and 2-methylaminoethanol in dry tetrahydrofuran (100 ml) was boiled under reflux for 3 hours. The solution was cooled, water (200 ml) was added, the mixture extracted with dichloromethane, the organic extracts were dried (MgSO4), filtered and evaporated to dryness. The residual oil was used in Preparation 5 without further purification. 0166 1H NMR (CDCl3) 0167 3.2 (3H, s); 3.5-3.9 (4H, m); 4.6 (1H, s, exchanges with D2O); 6.4 (1H, t); 8.2 (2H, d). 0168 Preparation 7 0169 2-N-Methyl-N-(2-4,5-dimethylthiazolyl)aminoethanol 22

0170 A solution of 2-chloro-4,5-dimethylthiazole (13.2 g) and 2-methylaminoethanol (40 ml) in pyridine (100 ml) was boiled under reflux for 20 hours. After cooling, the oil was added to water (300 ml) and extracted with ethyl acetate (3200 ml). The organic extracts were washed with brine (2200 ml), dried (MgSO4), filtered and evaporated to dryness to leave the title compound which was used in Preparation 14 without further purification. 0171 1H NMR (CDCl3) 0172 2.15 (3H, s); 2.20 (3H, s); 3.1 (3H, s); 3.4-3.9 (4H, m); 5.25 (1H, broad s, exchanges with D2O). 0173 Preparation 8 0174 2-N-Methyl-N-(2-thiazolyl)aminoethanol 23

0175 The title compound was prepared as an oil from 2-bromothiazole (15 g) and 2-methylaminoethanol (45 ml) by an analogous procedure to that described in Preparation 7 0176 1H NMR (CDCl3) 0177 3.1 (3H, s); 3.4-3.9 (4H, m); 4.8 (1H, broad s, exchanges with D20); 6.4 (1H, d); 7.0 (1H, d). 0178 Preparation 9 0179 2-N-Methyl-N-(2-(4-phenylthiazolyl) )aminoethanol 24

0180 The title compound was prepared as an oil from 2-chloro-4-phenylthiazole (13.5 g) and 2-methylaminoethanol (40 ml) by an analogous procedure to that described in Preparation 7. 0181 1H NMR (CDCl3) 0182 3.15 (3H, s); 3.6-4.0 (4H, m); 4.6 (1H, broad s, exchanges with D20); 6.7 (1H, s); 7.2-7.9 (5H, complex). 0183 Preparation 10 0184 2-N-Methyl-N-(2-(4-phenyl-5-methylthiazolyl))aminoethanol 25

0185 The title compound was prepared as an oil from 2-chloro-4-phenyl-5-methylthiazole (18.9 g) and 2-methylaminoethanol (50 ml) by an analogous procedure to that described in Preparation 7. 1H NMR (CDCl3) 0186 2.38 (3H, s); 3.0 (3H, s); 3.45-3.85 (4H, m); 5.1 (1H, broad s, exchanges with D2O); 7.1-7.7 (5H, complex). 0187 Preparation 11 0188 2-N-Methyl-N-(2-(4-methyl-5-phenylthiazolyl))amino-ethanol 26

0189 The title compound was prepared as an oil from 2-chloro-4-methyl-5-phenylthiazole (14.8 g) and 2-methylaminoethanol (40 ml) by an analogous procedure to that described in Preparation 7. 0190 1H NMR (CDCl3) 0191 2.35 (3H, s); 3.1 (3H, s); 3.5-4.0 (4H, m); 5.1 (1H, broad s, exchanges with D2O); 7.1-7.5 (5H, complex). 0192 Preparation 12 0193 2-N-Methyl-N-(2-(4-methylthiazolyl))aminoethanol 27

0194 The title compound was prepared, by an analogous procedure to that described in Preparation 7, and was used in the next stage without further purification. 0195 1H NMR (CDCl3) 0196 2.25 (3H, s); 3.1 (3H, s); 3.55-3.95 (4H, m); 4.9 (1H, broad s, exchanges with D2O); 6.1 (1H, 3). 0197 Preparation 13 0198 2-N-Methyl-N-2-(5-henyloxazolyl)aminoethanol 28

0199 A solution of 2-chloro-5-phenyloxazole (8.3 g) and 2-methylaminoethanol (30 ml) was stirred at 50 C. for 10 minutes. After cooling the oil was added to water (250 ml) and extracted with ethyl acetate (2150 ml). The organic extracts were washed with brine (2100 ml), dried (MgSO4), filtered and evaporated to dryness to leave the title compound (m.p. 73-75 C.). 0200 1H NMR (CDCl3) 0201 3.2 (3H, S); 3.6 (2H, t); 3.85 (2H, t); 3.9 (1H, broad s, exchanges with D2O); 7.0 (1H, s); 7.2-7.55 (5H, complex). 0202 Preparation 14 0203 4-2-(N-Methyl-N-(2-(4,5-dimethylthiazolyl)amino) ethoxy)benzaldehyde 29

0204 The title compound was prepared from 2-N-methyl-N-(2-(4,5-dimethylthiazolyl))aminoethanol (13.2 g) and 4-fluorobenzaldehyde (23.1 g) by an analogous procedure to that described in Preparation 5. 0205 1H NMR (CDCl3) 0206 2.15 (3H, s); 2.2 (3H, s); 3.18 (3H, s); 3.8 (2H, t); 4.3 (2H, t); 7.0 (2H, d); 7.8 (2H, d); 10.0 (1H, s). 0207 Preparation 15 0208 4-2-(N-Methyl-N-(2-thiazolyl)amino)ethoxybenzaldehyde 30

0209 The title compound was prepared from 2-N-methyl-N-(2-thiazolyl)aminoethanol (10.7 g) and 4-fluorobenzaldehyde (15.9 g) by an analogous procedure to that described in Preparation 5. 0210 1H NMR (CDCl3) 0211 3.15 (3H, s); 3.9 (2H, t); 4.4 (2H, t); 6.5 (1H, d); 7.0 (2H, d); 7.15 (1H, d); 7.8 (2H, d); 9.9 (1H, s). 0212 Preparation 16 0213 4-2-(N-Methyl-N-(2-(4-phenylthiazolyl)amino)ethoxy) benzaldehyde 31

0214 The title compound was prepared from 2-N-methyl-N-(2-(4-phenylthiazolyl))aminoethanol (16.1 g) and 4-fluorobenzaldehyde (17.4 g) by an analogous procedure to that described in Preparation 5. 0215 1H NMR (CDCl3) 0216 3.2 (3H, s); 3.95 (2H, t); 4.3 (2H, t); 6.7 (1H, s); 6.95-7.9 (9H, complex); 9.9 (1H, s). 0217 Preparation 17 0218 4-2-(N-Methyl-N-(2-(4-phenyl-5-methylthiazolyl)amino) ethoxy)benzaldehyde 32

0219 The title compound was prepared from 2-N-methyl-N-(2-(4-phenyl-5-methylthiazolyl))aminoethanol (13 g) and 4-fluorobenzaldehyde (9.8 g) by a similar procedure to that described in Preparation 5. 0220 1H NMR (CDCl3) 0221 2.35 (3H, s); 3.1 (3H, S); 3.8 (2H, t); 4.2 (2H, t); 6.85-7.8 (9H, complex); 9.85 (1H, S). 0222 Preparation 18 0223 4-2-(N-Methyl-N-(2-(4-methyl-5-phenyl-thiazolyl)amino) ethoxy)benzaldehyde 33

0224 The title compound was prepared from 2-N-methyl-N-(2-(4-methyl-5-phenylthiazolyl))aminoethanol (13 g) and 4-fluorobenzaldehyde (13 g) by an analogous procedure to that described in Preparation 5. 0225 1H NMR (CDCl3) 0226 2.36 (3H, s); 3.2 (3H, s); 3.9 (2H, t); 4.35 (2H, t); 7.05 (2H, d); 7.2-7.5 (5H, complex); 7.85 (2H, d); 9.95 (1H, s). 0227 Preparation 19 0228 4-2-(N-Methyl-N-(2-(4-methylthiazolyl))amino)ethoxybenzaldehyde 34

0229 The title compound was prepared from 2-N-methyl-N-(2-(4-methylthiazolyl))aminoethanol (12 g) and 4-fluorobenzaldehyde (14.3 g) by an analogous procedure to that described in Preparation 5. 0230 1H NMR 4 (CDCl3) 0231 2.25 (3H, s); 3.2 (3H, s); 3.9(2H, t); 4.3 (2H, t); 6.1 (1H, s); 7.05 (2H, d); 7.85 (2H, d); 9.95 (1H, s). 0232 Preparation 20 0233 4-2-(N-Methyl-N-2-(5-phenyloxazolyl)amino)ethoxybenzaldehyde 35

0234 The title compound was prepared from 2-N-methyl-N-(2-(5-phenyloxazolyl))aminoethanol (9.3 g) and 4-fluorobenzaldehyde (7.9 g) by an analogous procedure to that described in Preparation 5. 0235 1H NMR (CDCl3) 0236 3.25 (3H, s); 3.85 (2H, t); 4.3 (2H, t); 6.95-7.6 (8H, complex); 7.8 (2H, d); 9.9 (1H, s). 0237 Preparation 21 0238 2-N-Methyl-N-2-(4,5-dimethyloxazolyl)aminoethanol. 36

0239 A solution of 2-chloro-4,5-dimethyloxazole (5 g) and 2-methylaminoethanol (15 ml) was stirred at 120 C. for 40 minutes. After cooling the oil was added to water (200 ml) and extracted with dichloromethane (3200 ml). The organic extracts were washed with brine (2100 ml), dried (MgSO4), filtered and evaporated to dryness to leave the title compound as a waxy solid, which was used in Preparation 22 without further purification. 0240 1H NMR (CDCl3) 0241 1.95 (3H, s); 2.10 (3H, s); 3.05 (3H, s); 3.5 (2H, t); 3.8 (2H, t); 4.4 (1H, broad s, exchanges with D2O). 0242 Preparation 22 0243 4-2-(N-Methyl-N-2-(4,5-dimethyloxazolyl)amino) ethoxybenzaldehyde 37

0244 To a stirred solution of 2-N-methyl-N-2-(4,5-dimethyloxazolyl)aminoethanol (2.7 g) in DMF (60 ml), under an atmosphere of nitrogen, was added portionwise sodium hydride (0.7 g; 60% dispersion in oil). After the vigorous reaction had subsided, 4-fluorobenzaldehyde (2.9 g) was added and the reaction mixture was heated to 80 C. for 16 hours. After cooling, the mixture was added to water (400 ml). The aqueous solution was extracted with diethyl ether (3250 ml). The organic extracts were washed with brine (2100 ml), dried (MgSO4), filtered and evaporated to dryness. The title compound was obtained as an oil following chromatography of the residue on silica-gel in 1% methanol in dichloromethane. 0245 1H NMR (CDCl3) 0246 1.95 (3H, s); 2.15 (3H, s); 3.15 (3H, s); 3.8 (2H, t); 4.25 (2H, t); 7.0 (2H, d); 7.9 (2H, d); 10.0 (1H, s). 0247 Preparation 23 0248 2-(N-(2-Benzoxazolyl)-N-methylamino)ethanol 4-toluenesulphonyl ester 38

0249 4-Toluenesulphonyl chloride (19.0 g) was added portionwise to a solution of N-(2-benzoxazolyl)-N-methylaminoethanol (19.2 g) in dry pyridine (100 ml) at room temperature. The mixture was stirred at room temperature for 3 hours, added to water (500 ml) and extracted with dichloromethane (3250 ml). The combined extracts were washed with 2M hydrochloric acid (3250 ml), saturated sodium bicarbonate solution (250 ml) and brine (250 ml), dried (MgSO4), filtered and evaporated. The title compound was obtained pure following crystallisation from ethanol (m.p. 119-121 C.). 0250 1H NMR (DMSO-d6) 0251 2.25 (3H, s); 3.05 (3H, s); 3.75 (2H, t); 4.35 (2H, t); 7.0-7.4 (6H, complex); 7.70 (2H, d). 0252 Preparation 24 0253 2-(N-(2-Benzoxazolyl)-N-methylamino)ethanol methanesulphonyl ester 39

0254 The title compound (m.p. 97-8 C.) was prepared from N-(2-benzoxazolyl)-N-methylaminoethanol (19.2 g) and methanesulphonyl chloride (11.5 g) by a similar procedure to that used in Preparation 23. 0255 1H NMR (CDCl3) 0256 2.90 (3H, S); 3.25 (3H, s); 3.7 (2H, t); 4.5 (2H, t); 6.90-7.4 (4H, complex). 0257 Preparation 25 0258 4-2-(N-Methyl-N-(2-benzoxazolyl)amino)ethoxy-benzaldehyde 40

0259 To a solution of 4-hydroxybenzaldehyde (7.32 g) in dry dimethylformamide (100 ml) was added portionwise sodium hydride (60%, 2.4 g) with stirring at room temperature under nitrogen. When gas evolution ceased a solution of 2-(N-methyl-N-(2-benzoxazolyl)amino)ethanol 4-toluenesulphonyl ester (17.3 g) in dry dimethylformamide was added dropwise. The mixture was heated to 80 C. and stirred at this temperature overnight. After cooling, the solution was poured into iced water (1 liter), extracted with ethyl acetate (3500 ml), and the combined extracts were washed with sodium hydroxide solution (2M; 500 ml) and brine (500 ml), dried (MgSO4), filtered and evaporated. The title compound (m.p. 96-98 C.) was obtained pure after crystallisation from ethanol. 0260 1H H NMR (DMSO-d6) 0261 3.25 (3H, s); 3.95 (2H, t); 4.40 (2H, t); 6.90-7.40 (6H, complex); 7.85 (2H, d); 9.90 (1H, s). 0262 Preparation 26 0263 4-2-(N-Methyl-N-(2-benzoxazolyl)amino)ethoxybenzaldehyde 41

0264 The title compound was prepared from 4-hydroxy benzaldehyde (1.22 g) and 2-(N-methyl-N-(2-benzoxazolyl) -amino)ethanol methanesulphonyl ester (2.7 g) in a similar manner to that described in Preparation 25. 0265 Preparation 27 0266 2-(2-Pyrimidinylamino)ethanol 42

0267 2-Chloropyrimidine (5 g) and ethanolamine (l5 ml) were stirred for 2 hours at 140 C. After cooling, the mixture was added to water (200 ml) and continuously extracted with ethyl acetate (500 ml) for 16 hours. The organic extract was dried (MgSO4), filtered and evaporated to dryness. The title compound was obtained as a solid (m.p. 66 C.), following chromatography on silica-gel in 3% methanol in dichloromethane. 0268 1H NMR (CDCl3) 0269 3.55 (2H, complex); 3.8 (2H, t); 4.3 (1H, broad s, exchanges with D2O); 6.1 (1H, broad s, exchanges with D2O); 6.55 (1H, t); 8.3 (2H, d). 0270 Preparation 28 0271 4-f2-(2-Pyrimidinylamino)ethoxybenzaldehyde 43

0272 Sodium hydride (1.2 g; 60% dispersion in oil) was added portionwise to a stirred solution of 2-(2-pyrimidinyl amino)ethanol (4 g) in DMF (140 ml) under an atmosphere of nitrogen. After the vigorous reaction had subsided 4-fluorobenzaldehyde (5.35 g) was added and the solution heated to 80 C. for 20 hours. After cooling the mixture was added to water (500 ml) and extracted with diethyl ether (3300 ml). The organic extracts were washed with brine (2200 ml), dried (MgSO4), filtered and evaporated to dryness. Chromatography of the residue on silica gel in 2% methanol in dichloromethane afforded the title compound, which was used in the next stage without further purification. 0273 1H NMR (CDCl3) 0274 3.8 (2H, complex); 4.2 (2H, t); 5.7 (1H, broad s, exchanges with D2O); 6.5 (1H, t); 7.0 (2H, d); 7.8 (2H, d); 8.3 (2H, d); 9.9 (1H, S). 0275 Preparation 29 0276 2-(N-(2-Benzothiazolyl)-N-benzylamino)ethanol 44

0277 2-Chlorobenzothiazole (13 g) and 2-(benzylamino)ethanol (29 g) were heated together in a sealed vessel at 120 C. for 20h.. After cooling, the reaction mixture was dissolved in ethyl acetate (200 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate (3100 ml), water (3100 ml) and brine (100 ml), dried over anhydrous magnesium sulphate and evaporated to give the title compound (m.p. 95-96 C.; dichloromethane/hexane). 0278 1H NMR (CDCl3) 0279 3.8 (4H, m); 4.5 (1H, broad s, exchanges with D2O); 4.7 (2H, s); 6.9-7.7 (9H, complex). 0280 Preparation 30 0281 4-(2-(N-(2-Benzothiazolyl)-N-benzylamino)ethoxy)benzaldehyde 45

0282 The title compound was prepared from 2-(N-(2-benzothiazolyl)-N-benzylamino)ethanol (8.25 g) and 4-fluorobenzaldehyde (3.6 g) by an analogous procedure to that described in Preparation 22. 0283 1H NMR (CDCl3) 0284 4.0 (2h, t); 4.4 (2H, t); 4.9 (2H, s); 6.9-8.0 (13H, complex); 10.0 (1H, s). 0285 Preparation 31 0286 4-3-(N-Methyl-N-(2-benzoxazolyl)-amino)propoxybenzaldehyde 46

0287 The title compound was prepared from 3-(N-(2-benzoxazolyl)-N-methyl)aminopropan-1-ol (7.5 g) and 4-fluorobenzaldehyde (6.78 g) by a similar procedure to that described in Preparation 22. 0288 1H NMR (CDCl3) 0289 2.0-2.4 (2H, complex); 3.2 (3H, S); 3.75 (2H, t); 4.2 (2H, t); 6.8-7.5 (6H, complex); 7.8 (2H, d); 9.9 (1H, s). 0290 Preparation 32 0291 3-(N-(2-Benzoxazolyl)-N-methyl)amino)propan-1-ol 47

0292 2-Chlorobenzoxazole (15.36 g) in dry tetrahydrofuran (50 ml) was added dropwise to a mixture of 3-N-methylaminopropan-1-ol (9.8 g) and triethylamine (20.2 g) in dry tetrahydrofuran (130 ml) with stirring, at room temperature. After stirring at room temperature overnight the solvent was evaporated. The residue was dissolved in dichloromethane (150 ml), washed with water (3100 ml), brine (150 ml), dried (MgSO4), filtered and evaporated. The title compound was obtained as an oil following chromatography on silica-gel in 2.5-3% methanol in dichloromethane. 0293 1H NMR (CDCl3) 0294 1.8-2.1 (2H, complex); 3.2 (3H, s); 3.5-3.85 (4H, complex); 4.3 (1H, broad s, exchanges with D2O); 6.8-7.5 (4H, complex). 0295 Preparation 33 0296 4-2-(N-Methyl-N-(2-pyridyl)amino)ethoxybenzaldehyde 48

0297 The title compound was prepared from 2-(N-methyl-N-(2-pyridyl)amino)ethanol (8.9 g) and 4-fluorobenzaldehyde by a similar procedure to that described in Preparation 22. 0298 1H NMR (CDCl3) 0299 3.2 (3H, s); 3.8 (2H, t); 4.2 (2H, t); 6.4 (2H, t); 6.9 (2H, d); 7.3 (1H, complex); 7.75 (2H,d); 8.15 (1H,d); 9.9 (1H, s). 0300 Preparation 34 0301 4-N-(2-Benzoxazolyl)-N-methylaminobutan-1-ol 49

0302 2-Chlorobenzoxazole (15.35 g) was added dropwise over 10 minutes to a stirred solution of 4-(N-methylamino)butan-1-ol (10.3 g) and triethylamine (20.3 g) in dry tetrahydrofuran (150 ml). The mixture was stirred at room temperature overnight, and then heated at reflux for a further 2h. The resulting mixture was cooled and the solvent was evaporated. The residue was dissolved in dichloromethane (500 ml), washed with saturated sodium bicarbonate solution (3300 ml) and brine (500 ml), dried and evaporated to afford the title compound as an oil. 0303 1H NMR (CDCl3) 0304 1.5-2.0 (4H, complex); 3.1 (3H,s); 3.4-3.9 (5H, complex; reduced to 4H after D20 exchange); 6.9-7.4 (4H, complex) 0305 Preparation 35 0306 4-(N-(2-Benzoxazolyl)-N-methyl)aminobutan-1-ol methanesulphonyl ester 50

0307 Methanesulphonyl chloride (3.15 g) was added dropwise to a stirred, ice-cooled solution of 4-N-(2-benzoxazolyl)-N-methylaminobutan-1-ol (5.5 g) and 4-dimethylaminopyridine (0.15 g) in pyridine (100 ml). The mixture was allowed to warm to room temperature overnight, and then diluted with water (500 ml), and extracted with dichloromethane (3200 ml). The combined extracts were washed with saturated sodium bicarbonate solution (3200 ml), and brine (200 ml), then dried and the solvent evaporated to afford an oil. More of this oil was obtained from the acidic aqueous layers by means of adjusting the pH to 4.5 with solid potassium carbonate, re-extracting with dichloromethane (3200 ml), and drying and evaporating these dichloromethane layers. The combined impure product fractions were chromatographed on silica gel with 2% methanol in dichloromethane as eluent to afford the title compound as an oil. 0308 1H NMR (CDCl3) 0309 1.80(4H,complex); 3.05(3H,s); 3.25(3H,s); 3.60(2H,complex); 4.30(2H,complex); 6.90-7.40(4H, complex). 0310 Preparation 36 0311 4-4-(N-Methyl-N-(2-benzoxazolyl)amino)butoxybenzaldehyde 51

0312 The title compound was prepared from 4-hydroxybenzaldehyde (1.71 g) and 4-N-(2-benzoxazolyl)-N-methylaminobutan-1-ol methanesulphonyl ester (3.80 g) by a similar procedure to that used in Preparation 26. 0313 1H NMR (CDCl3) 0314 1.70-1.95(4H, complex); 3.20(3H,s); 3.55(2H, complex); 4.00(2H, complex); 6.80-7.40(6H, complex) 7.75(2H,d); 9.90(1H,s) 0315 Preparation 37 0316 2-N-(2-Benzoxazolyl)aminoethanol 52

0317 A solution of 2-chlorobenzoxazole (12.78 g) in dry tetrahydrofuran (50 ml) was added, over 10 minutes, to a stirred, ice-cooled solution of ethanolamine (15.3 g) in dry tetrahydrofuran (400 ml). The mixture was heated at reflux overnight, cooled, and the solvent evaporated. The residue was partitioned between water (500 ml) and dichloromethane (500 ml), and the resulting white solid filtered off, washed with dichloromethane and dried in vacuo to afford the title compound m.p. 162-4 C. 0318 1H NMR DMSO-d6 0319 3.3-3.8 (4H, complex); 5.0 (1H, br, exchanges with D2O); 6.9-7.7 (4H, complex); 8.1 (1H, br, exchanges with D2O). 0320 Preparation 38 0321 2-N-(2-Benzoxazolyl)aminoethanol methanesulphonyl ester 53

0322 Methanesulphonyl chloride (4.9 g) was added dropwise to a stirred, ice-cooled solution of 2-N-(2-benzoxazolyl)aminoethanol (6.23 g) and triethylamine (4.39 g) in dichloromethane (75 ml). The resulting mixture was stirred at 0 C. for 1.5h and then diluted with dichloromethane (200 ml), washed with water (2200 ml), brine (200 ml) and dried. The dichloromethane layer was evaporated and the residue chromatographed on silica gel with 1.5% methanol in dichloromethane as eluent to give the title compound, m.p. 96-9 C. 0323 1H NMR CDCl3 0324 3.0 (3H,s); 3.85 (2H,t); 4.5 (2H,t); 5.9 (1H,br, exchanges with D2O); 7.0-7.5 (4H, complex). 0325 Preparation 39 0326 4-2-(N-(2-Benzoxazolyl)aminoethoxybenzaldehyde 54

0327 A mechanically stirred mixture of 2-N-(2-benzoxazolyl)aminoethanol methanesulphonyl ester (5.77 g), 4-hydroxybenzaldehyde (2.81 g) and potassium carbonate (3.28 g) was heated at 80 C. overnight in dry DMF (250 ml). After cooling, the reaction mixture was concentrated in vacuo, diluted with water (500 ml) and extracted with ethyl acetate (3300 ml). The combined ethyl acetate layers were washed with water (21l), brine (1l), dried and evaporated. The resulting solid was chromatographed on silica gel with 1.5% methanol in dichloromethane as eluent to afford the title compound, m.p. 103-6 C. 0328 1H NMR CDCl3 0329 3.9 (2H,t); 4.3 (2H,t); 6.4(1H, br, exchanges with D2O); 6.9-8.0 (8H, complex); 9.9 (1H,s). 0330 Preparation 40 0331 2-N-Isopropyl-N-(2-benzoxazolyl)aminoethanol 55

0332 2-Chlorobenzoxazole (23.04 g) was added dropwise to an ice-cooled solution of 2-(isopropylamino)ethanol (15.45 g) and triethylamine (30.3 g) in tetrahydrofuran (500 ml). The mixture was stirred at room temperature for 30 minutes, then heated at reflux overnight before being cooled and evaporated. The residue was dissolved in dichloromethane (800 ml) and washed with saturated sodium bicarbonate solution (500 ml), water (31l) brine (1l), dried (MgSO4), filtered and evaporated. The title compound was obtained as an oil following chromatography on silica gel using 1.5% methanol-dichloromethane as solvent. 0333 1H NMR (CDCl3) 0334 1.25 (6H,d); 3.6 (2H,t); 3.9 (2H,t); 4.5 (1H,m); 4.55 (1H, broad s, exchanges with D2O); 6.95 - 7.50 (4H, complex). 0335 Preparation 41 0336 2-N-Isopropyl-N-(2-benzoxazolyl)aminoethanol methanesulphonyl ester. 56

0337 The title compound was prepared from 2-N-isopropyl -N-(2-benzoxazolyl)aminoethanol and methanesulphonyl chloride by a similar procedure to that described in Preparation 38. 0338 1H NMR (CDCl3) 0339 1.35 (6H,d); 3.0 (3H,s); 3.8 (2H,t); 4.3-4.7 (3H, complex); 6.9-7.5 (4H, complex).

EXAMPLE 1 0340 5-(4-2-(N-Methyl-N-(2-benzothiazolyl)amino)ethoxybenzyl)-2,4-thiazolidinedione. 57

0341 5-(4-2-(N-Methyl-N-(2-benzothiazolyl)amino)ethoxybenzylidene)-2,4-thiazolidinedione (2 g) in dry 1,4-dioxan (70 ml) was reduced under hydrogen in the presence of 10% palladium on charcoal (3 g) at ambient temperature and atmospheric pressure until hydrogen uptake ceased. The solution was filtered through diatomaceous earth, the filter pad was washed exhaustively with dioxan and the combined filtrates were evaporated to dryness under vacuum. The title compound (m.p. 167-8 C.) was obtained after crystallisation from methanol. 0342 1H NMR (DMSO-d6) 0343 2.9-3.4 (2H, complex); 3.25 (3H, s); 3.9 (2H, complex); 4.25 (2H, complex); 4.8 (1H, complex); 6.8-7.75 (8H, complex); 12.0 (1H, s, exchanges with D2O).

EXAMPLE 2 0344 5-(4-2-(N-Methyl-N-(2-benzothiazolyl)amino)ethoxybenzylidene)-2,4-thiazolidinedione. 58

0345 A solution of 4-2-(N-methyl-N-(2-benzothiazolyl)amino) ethoxybenzaldehyde (1.9 g) and 2,4-thiazolidinedione (0.8 g) in toluene (100 ml) containing a catalytic quantity of piperidinium acetate was boiled under reflux in a Dean and Stark apparatus for 2 hours. The mixture was cooled and filtered and the filtered solid was dried to give the title compound (mp 219 C.). 0346 1H NMR (DMSO-d6) 0347 3.2 (3H, s); 3.9 (2H, t); 4.35 (2H, t); 6.8-7.7 (10H, complex).

EXAMPLE 3 0348 5-(4-2-(N-Methyl-N-(2-benzoxazolyl)amino)ethoxybenzyl)-2,4-thiazolidinedione hemihydrate 59

0349 5-(4-2-(N-Methyl-N-(2-benzoxazolyl)amino)ethoxy-benzylidene)-2,4-thiazolidinedione (1.5 g) in dry 1,4-dioxan (80 ml) was reduced under hydrogen in the presence of 10% palladium on charcoal (2 g) at ambient temperature and atmospheric pressure until hydrogen uptake ceased. The solution was filtered through diatomaceous earth, the filter pad was washed exhaustively with dioxan and the combined filtrates were evaporated to dryness under vacuum. The title compound (mp 147-9 C.) was obtained after crystallisation from methanol. 0350 1H NMR (DMSO-d6D2O) 0351 3.1-3.5 (2H, complex); 3.3 (3H,s); 3.95 (2H, complex); 4.25 (2H, complex); 4.5 (1H, complex); 6.8-7.3 (8H, complex).

EXAMPLE 4 0352 5-(4-2-(N-Methyl-N-(2-benzoxazolyl)amino)ethoxybenzylidene)-2,4-thiazolidinedione 60

0353 A solution of 4-12-(N-methyl-N-(2-benzoxazolyl)amino) ethoxybenzaldehyde (1.6 g) and 2,4-thiazolidinedione (0.63 g) in toluene (100 ml) containing a catalytic quantity of piperidinium acetate was boiled under reflux in a Dean and Stark apparatus for 2 hours. The mixture was cooled and filtered to give the title compound (mp 227-9 C.) 0354 1H NMR (DMSO-d6) 0355 3.20 (3H, s); 3.90 (2H, t); 4.30 (2H, t); 6.9-7.75 (10H, complex).

EXAMPLE 5 0356 5-(4-2-(N-Methyl-N-(2-pyrimidinyl)amino)ethoxybenzyl)-2,4-thiazolidinedione 61

0357 5-(4-2-(N-Methyl-N-(2-pyrimidinyl)amino) ethoxybenzylidene)-2,4-thiazolidinedione (2.4 g) in dry 1,4-dioxan (150 ml) was reduced under hydrogen in the presence of 10% palladium on charcoal (3 g) until hydrogen uptake ceased. The solution was filtered through diatomaceous earth, the filter pad was washed exhaustively with dioxan and the combined filtrates were evaporated to dryness under vacuum. The title compound (mp 150-51 C.) was obtained after crystallisation from methanol. 0358 1H NMR (DMSO-d6) 0359 2.9-3.4 (2H, complex); 3.2 (3H, s); 3.9 (2H, complex); 4.2 (2H, complex); 4.9 (1H, complex); 6.6 (1H, t); 6.9 (2H, d); 7.2 (2H, d); 8.4 (2H, d); 12.0 (1H, broad s, exchanges with D2O).

EXAMPLE 6 0360 5-(4-2-(N-Methyl-N-(2-pyrimidinyl)amino)ethoxybenzylidene)-2,4-thiazolidinedione 62

0361 A solution of 4-2-(N-methyl-N-(2-pyrimidinyl)amino) ethoxybenzaldehyde (1.7 g) and 2,4-thiazolidinedione (0.7 g) in toluene (100 ml) containing a catalytic quantity of piperidinium acetate was boiled under reflux in a Dean and Stark apparatus for 2 hours. The mixture was cooled and filtered to give the title compound (mp 189-90 C.). 0362 1H NMR (DMSO-d6D2O) 0363 3.2 (3H, s); 3.7-4.4 (4H, complex); 6.6 (1H, t); 7.1 (2H, d), 7.5 (2H, d); 7.7 (1H, s); 8.4 (2H, d).

EXAMPLE 7 0364 5-(4-(2-(N-Methyl-N-2-(4,5-dimethylthiazolyl)amino) ethoxybenzyl)-2,4-thiazolidinedione 63

0365 5-(4-2-(N-Methyl-N-2-(4,5-dimethylthiazolyl)amino) ethoxybenzylidene-2,4-thiazolidinedione (1.6 g) was dissolved in a mixture of methanol (50 ml) and dioxan (50 ml). Magnesium turnings (1.5 g) were added and the solution stirred until no more effervescence was observed. The mixture was added to water (300 ml), acidified (2M HCl) to form a solution, neutralised (saturated NaHCO3 solution), filtered and dried. The solid was dissolved in dioxan (100 ml), adsorbed onto silica (20 g) and the title compound (m.p. 177 C.; MeOH) obtained following chromatography on silica-gel in 5% dioxan in dichloromethane. 0366 1H NMR (DMSO-d6) 0367 2.05 (3H, s); 2.15 (3H, s); 3.0 (3H, s); 3.0-3.4 (2H, complex); 3.8 (2H, t); 4.2 (2H, t); 4.85 (1H, complex); 6.9 (2H, d); 7.1 (2H, d); 12.0 (1H, broad s exchanges with D2O).

EXAMPLE 8 0368 5-(4-2-(N-Methyl-N-2-(4,5-dimethylthiazolyl)amino) ethoxybenzylidene)-2,4-thiazolidinedione 64

0369 The title compound (m.p. 175 C.) was prepared by a similar procedure to that described in Example 4. 0370 1H NMR (DMSO-d6) 0371 2.0 (3H, s); 2.1 (3H, s); 3.0 (3H, s); 3.7 (2H, t); 4.25 (2H, t); 7.1 (2H, d); 7.55 (2H, d); 7.75 (1H, s); 12.0 (1H, broad s, exchanges with D2O).

EXAMPLE 9 0372 5-(4-2-(N-Methyl-N-(2-thiazolyl)aminoethoxyben -2,4-thiazolidinedione 65

0373 The title compound (m.p. 186 C.; MeOH) was prepared by an analogous procedure to that described in Example 7. 0374 1H NMR (DMSO-d6) 0375 3.0-3.4 (2H, complex); 3.1 (3H, s); 3.8 (2H, t); 4.2 (2H, t); 4.85 (1H, complex); 6.7-7.3 (6H, complex); 12.0 (1H, broad s, exchanges with D2O).

EXAMPLE 10 0376 5-(4-2-(N-Methyl-N-(2-thiazolyl)amino)ethoxybenzylidene)-2,4-thiazolidinedione 66

0377 The title compound (m.p. 212 C.) was prepared by a similar procedure to that described in Example 4. 0378 1H NMR (DMSO-d6) 0379 3.1 (3H, S); 3.85 (2H, t); 4.3(2H, t); 6.75 (1H, d); 7.1-7.3 (3H, complex); 7.6 (2H, d); 7.75 (1H, s); 12.0 (1H, broad s, exchanges with D2O).

EXAMPLE 11 0380 5-4-(2-(N-Methyl-N-(2-(4-phenylthiazolyl))amino) ethoxy)benzyl-2,4-thiazolidinedione 67

0381 The title compound was obtained as a foam (m.p. 62-65 C.) from 5-4-(2-(N-methyl-N-(2-(4-phenylthiazolyl))amino)ethoxy)benzylidene-2,4-thiazolidinedione (1.6 g) by a similar procedure to that described in Example 7. 0382 1H NMR (DMSO-d6) 0383 3.15 (3H, s); 3.0-3.4 (2H, complex); 3.9 (2H, t); 4.25 (2H, t); 4.85 (1H complex); 6.9 (2H, d); 7.1-7.45 (6H, complex); 7.85 (2H, d); 12.0 (1H, broad s, exchanges with D2O).

EXAMPLE 12 0384 5-(4-2-(N-Methyl-N-(2-(4-phenylthiazolyl))amino) ethoxybenzylidene)-2,4-thiazolidinedione 68

0385 The title compound (m.p. 134 C.) was prepared from 4-2-(N-methyl-N-(2-(4-phenylthiazolyl))amino)ethoxy benzaldehyde by a similar procedure to that described in Example 4. 0386 1H NMR (DMSO-d6) 0387 3.2 (3H, 3); 3.9 (2H, t); 4.35 (2H, t); 7.1-7.95 (11H, complex); 12.0 (1H broad s, exchanges with D2O).

EXAMPLE 13 0388 5-(4-2-(N-Methyl-N-f2-(4-phenyl-5-methylthiazolyl)amino)ethoxybenzyl)-2,4-thiazolidinedione 69

0389 The title compound, obtained as a foam (m.p. 60-62 C.), was prepared by an analogous procedure to that described in Example 7. 0390 1H NMR (DMSO-d6) 0391 2.35 (3H, s); 3.1 (3H, s); 3.0-3.4 (2H, complex); 3.8 (2H, t); 4.2 (2H, t); 4.85 (1H, complex); 6.9 (2H, d); 7.2 (2H, d); 7.25-7.5 (3H, complex); 7.65 (2H, d); 12.0 (1H, broad s, exchanges with D2O).

EXAMPLE 14 0392 5-(4-2-(N-Methyl-N-2-(4-phenyl-5-methylthiazolyl)l amino)ethoxybenzylidene)-2,4-thiazolidinedione 70

0393 The title compound was prepared from 4-2-(N-methyl-N-2-(4-phenyl-5-methylthiazolyl)amino)ethoxybenzaldehyde by a similar procedure to that described in Example 4, and was used in Example 13 without further purification. 0394 1H NMR (DMSO-d6) 0395 2.4 (3H, s); 3.1 (3H, S); 3.8 (2H, t); 4.35 (2H, t); 7.1-7.75 (10H, complex); 12.0 (1H, broad s, exchanges with D2O).

EXAMPLE 15 0396 5-(4-2-(N-Methyl-N-2-(4-methyl-5-phenylthiazolyl)amino)ethoxybenzyl)-2,4-thiazolidinedione 71

0397 The title compound (m.p. 174 C.; MeOH) was prepared from 5-(4-2-(N-methyl-N-2-(4-methyl-5-phenylthiazolyl)-amino)ethoxybenzylidene)2,4-thiazolidinedione by an analogous procedure to that described in Example 7. 0398 1H NMR (DMSO-d6) 0399 2.3 (3H, s); 3.0-3.4 (2H, complex); 3.15 (3H, s); 3.85 (2H, t); 4.25 (2H, t); 4.85 (1H, complex); 6.95 (2H, d); 7.2 (2H, d); 7.45 (5H, complex); 12.0 (1H, broad s, exchanges with D2O).

EXAMPLE 16 0400 5-(4-2-(N-Methyl-N-2-(4-methyl-5-phenylthiazolyl)l amino)ethoxybenzylidene)-2,4-thiazolidinedione 72

0401 The title compound was prepared from 4-2-(N-methyl-N-2-(4-methyl-5-phenylthiazolyl)amino)ethoxybenzaldehyde by a similar procedure to that described in Example 4, and was used in Example 15 without further purification. 0402 1H NMR (DMSO-d6) 0403 2.3 (3H, s); 3.1 (3H, S); 3.85 (2H, t); 4.35 (2H, t); 7.15-7.75 (1OH, complex); 12.0 (1H, broad s, exchanges with D2O).

EXAMPLE 17 0404 5-(4-2-(N-Methyl-N-2-(4-methylthiazolyl)amino)ethoxybenzyl)-2,4-thiazolidinedione 73

0405 The title compound, was prepared from 5-(4-(2-(N-methyl -N-2-(4-methylthiazolyl)amino)ethoxybenzylidene)-2,4-thiazolidinedione as a foam (m.p. 121 C.), by a similar procedure to that described in Example 7. 0406 1H NMR (DMSO-d6) 0407 2.1 (3H, s); 3.0-3.4 (2H, complex); 3.1 (3H, s); 3.75 (2H, t); 4.15 (2H, t); 4.85 (1H, complex); 6.3 (1H, s); 6.9 (2H, d); 7.2 (2H, d); 12.0 (1H, broad s, exchanges with D2O).

EXAMPLE 18 0408 5-(4-2-(N-Methyl-N-f2-(4-methylthiazolyl)amino) ethoxybenzylidene)-2,4-thiazolidinedione 74

0409 The title compound was prepared from 5-(4-2-(N-methyl-N-2-(4-methylthiazolyl)amino)ethoxybenzaldehyde by a similar procedure to that described in Example 4, and was used in the Example 17 without further purification. 0410 1H NMR (DMSO-d6) 0411 2.1 (3H, s); 3.1 (3H, s); 3.85 (2H, d); 4.3 (2H, d); 6.3 (1H, s); 7.15 (2H, d); 7.6 (2H, d); 7.75 (1H, s); 12.0 (1H, broad s, exchanges with D2O).

EXAMPLE 19 0412 5-4-(2-(N-Methyl-N-2-(5-phenyloxazolyl)amino ethoxy)benzyl-2,4-thiazolidinedione 75

0413 The title compound (m.p. 200 C., MeOH)) was prepared from 5-4-(2-(N-methyl-N-2-(5-phenyloxazolyl)amino ethoxy)benzylidene-2,4-thiazolidinedione by a similar procedure to that described in Example 7. 0414 1H NMR (DMSO-d6) 0415 3.0-3.4 (2H, complex); 3.15 (3H, s); 3.8 (2H, t); 4.2 (2H, t); 4.85 (1H, complex); 6.9 (2H, d); 7.1-7.4 (6H, complex); 7.5 (2H, d); 12.0 (1H, broad s, exchanges with D2O).

EXAMPLE 20 0416 5-(4-2-(N-Methyl-N-2-(5-Phenyloxazolyl)amino) ethoxybenzylidene)-2,4-thiazolidinedione 76

0417 The title compound (m.p. 191 C.) was prepared from 4-2-(N-methyl-N-2-(5-phenyloxazolyl)amino) ethoxybenzaldehyde by an analogous procedure to that described in Example 4. 0418 1H NMR (DMSO-d6) 0419 3.2 (3H, s); 3.8 (2H, t); 4.35 (2H, t); 7.1-7.7 10H, complex); 7.8 (1H, s5); 12.0 (1H, broad s, exchanges with D2O).

EXAMPLE 21 0420 5-(4-2-(N-Methyl-N-2-(4,5-dimethyloxazolyl)amino) ethoxybenzyl)-2,4-thiazolidinedione 77

0421 5-(4-2-( N-methyl-N-2-(4,5-dimethyloxazolyl)amino)-ethoxybenzylidene)-2,4-thiazolidinedione (1.2 g) in dry 1,4-dioxan (100 ml) was-reduced under hydrogen in the presence of 10% Palladium on charcoal (2.5 g) until hydrogen uptake ceased. The solution was filtered through diatomaceous earth, the filter pad was washed exhaustively with dioxan and the combined filtrates evaporated to dryness under vacuum. The title compound was obtained as a foam (m.p. 53-54 C.) following chromatography on silica-gel in 1% methanol in dichloromethane. 0422 1H NMR (DMSO-d6) 0423 1.85 (3H, s); 2.05 (3H, s); 3.0 (3H, s); 16.6; 3.0-3.4 (2H, complex); 3.65 (2H, t); 4.1 (2H, t); 4.85 (1H, complex); 6.85 (2H, d); 7.15 (2H, d); 18 12.0 (1H, broad s, exchanges with D2O).

EXAMPLE 22 0424 5-(4-2-(N-Methyl-N-2-(4,5-dimethyloxazolyl)amino)-ethoxybenzylidene)-2,4-thiazolidinedione 78

0425 The title compound (softens at 149 C.) was prepared by a similar procedure to that described in Example 4. 0426 1H NMR (DMSO-d6) 0427 1.85 (3H, s); 2.05 (3H, s); 3.0 (3H, s); 3.7 (2H, t); 4.25 (2H, t); 7.1 (2H, d); 7.5 (2H, d); 7.75 (1H, s); 12.0 (1H, broad s, exchanges with D2O).

EXAMPLE 23 0428 5-4-(2-(2-Pyrimidinylamino)ethoxy)benzyl-2,4-thiazolidinedione 79

0429 A mixture of 5-(4-(2-(2-pyrimidinylamino)ethoxy) benzylidene-2,4-thiazolidinedione (3 g) and 10% palladium on charcoal (9 g) in DMF (70 ml) was stirred under a pressure of 200 psi of hydrogen until hydrogen uptake ceased. The mixture was filtered through diatomaceous earth, and the filter pad washed exhaustively with DMF. The combined filtrates were evaporated to dryness and the title compound (m.p. 173 C.) obtained following recrystallization from methanol. 0430 1H NMR (DMSO-d6) 0431 3.0-3.4 (2H, complex); 3.65 (2H, complex); 4.1 (2H, t); 4.85 (1H, complex); 6.6 (1H, t); 6.85 (2H, d); 7.15 (2H, d); 7.25 (1H, t, exchanges with D2O); 8.3 (2H, d); 12.0 (1H, broad s, exchanges with D2O).

EXAMPLE 24 0432 5-4-(2-(2-Pyrimidinylamino)ethoxy)benzylidene-2,4-thiazolidinedione 80

0433 The title compound (m.p. 234 C.) was obtained from 4-(2-(2-pyrimidinylamino)ethoxybenzaldehyde and 2,4-thiazolidindione, by an analogous procedure to that described in Example 6. 0434 1H NMR (DMSO-d6) 0435 3.65 (2H, complex); 4.2 (2H,t); 6.6 (1H, t); 7.0-7.6 (5H, complex, one pro ton changes with D2O); 7.7 (1H, s); 8.3 (2H, d); 12.0 (1H, broad s, exchanges with D2O).

EXAMPLE 25 0436 5-(4-2-(N-Acetyl-N-(2-pyrimidinyl)amino)ethoxybenzyl) -2,4-thiazolidinedione 81

0437 A stirred solution of 5-(4-(2-(2-pyrimidinylamino) ethoxy)benzyl-2,4-thiazolidinedione (800 mg) in acetic anhydride (15 ml) and 1,4-dioxan (5 ml) was boiled under reflux for 3 hours. After cooling, the mixture was added to water (300 ml), neutralized (sodium bicarbonate) and extracted with dichloromethane (3200 ml). The organic extracts were washed with brine (100 ml), dried (MgSO4), filtered and evaporated to dryness. Chromatography on silica-gel in dichloromethane of the residual oil afforded the title compound (m.p. 137 C.). 0438 1H NMR (DMSO-d6) 0439 2.3 (3H, s); 2.93.4 (2H, complex); 4.15 (2H,t); 4.35 (2H, t); 4.85 (1H, complex); 6.7 (2H,d); 7.1 (2H, d); 7.35 (1H, t); 8.8 (214, d); 12.0 (1H, broad s, exchanges with D2O).

EXAMPLE 26 0440 5-(4-(2-(N-(2-Benzothiazolyl)-N-benzylamino)ethoxy) benzylidene)-2,4-thiazolidinedione 82

0441 4-(2-(N-(2-Benzothiazolyl)-N-benzylamino)ethoxy) benzaldehyde (3 g) and 2,4-thiazolidinedione (1 g) were dissolved in toluene (200 ml) containing piperidine (0.2 ml) and benzoic acid (0.2 g) and heated to reflux for 4h. in a Dean and Stark apparatus. On cooling, the solution was concentrated under vacuum to 50% of its volume and the title compound, which crystallised, was collected by filtration and dried in vacuo (m.p. 185-188 C.). It was used in Example 27 without further purification. 0442 1H NMR (DMSO-d6) 0443 4.0 (2H, t); 4.4 (2H, t); 4.9 (2H, s); 7.1-7.9 (14H, complex); 12-13 (1H, broad s, exchanges with D2O).

EXAMPLE 27 0444 5-(4-(2-(N-(2-Benzothiazolyl) -N-benzylamino) ethoxy) benzyl)-2,4-thiazolidinedione 83

0445 5-(4-(2-(N-(2-Benzothiazolyl)-N-benzylamino)ethoxy) benzylidene)-2,4-thiazolidinedione (2.4 g) in dioxan (150 ml) was hydrogenated in the presence of 10% palladium-charcoal (4.8 g) for 3h. at room temperature and atmospheric pressure. A further portion of catalyst (2.4 g) was added and the hydrogenation continued for a total of 20h. The mixture was filtered through diatomaceous earth and the solvent was evaporated. The residue was chromatographed on silica gel with 3% methanol-dichloromethane as eluant to afford the title compound as a foam, which collapsed at 78 C. 0446 1H NMR (CDCl3) 0447 3.1 (1H, dd); 3.4 (1H, dd); 4.0 (2H, t); 4.25 (2H, t); 4.5 (1H, dd); 4.9 (2H, s); 6.8-7.6 (13H, m); 8.3 (1H, broad s, exchanges with D2O).

EXAMPLE 28 0448 5-(4-3-(N-Methyl-N-(2-benzoxazolyl)amino)propoxybenzyl)-2,4-thiazolidinedione 84

0449 The title compound (m.p. 171-3 C.; ethanol) was prepared from 5-(4-3-(N-methyl-N-(2-benzoxazolyl)amino)-propoxybenzylidene)-2-4-thiazolidinedione by a similar procedure to that described in Example 1. 0450 1H NMR (DMSO-d6) 0451 2.0-2.35 (2H, complex); 2.9-3.6 (2H, complex); 3.2 (3H, s); 3.7 (2H, t); 4.2 (2H, t); 4.9 (1H, complex); 6.8-7.4 (8H, complex); 12-12.5 (1H, broad s, exchanges with D2O).

EXAMPLE 29 0452 5-(4-3-(N-Methyl-N-(2-benzoxazolyl)amino)propoxyl-benzylidene)-2,4-thiazolidinedione 85

0453 The title compound (m.p. 202-204 C.) was prepared from 4-3-(N-methyl-N-(2-benzoxazolyl)amino)propoxybenzaldehyde (5.3 g) and 2,4-thiazolidinedione (2.2 g) by a similar procedure to that described in Example 4. 0454 1H NMR (DMSO-d6) 0455 2.0-2.35 (2H, complex); 3.15 (3H, s); 3.7 (2H, t); 4.2 (2H, t); 7.0-7.7 (8H, complex); 7.8 (1H, s); 12.0 (1H, broad s, exchanges with D2O).

EXAMPLE 30 0456 5-(4-2-(N-Methyl-N-(2-pyridyl)amino)ethoxybenzyl)-2,4-thiazolidinedione 86

0457 The title compound (m.p. 153-5 C.; MeOH) was obtained from 5-(4-2-(N-methyl-N-(2-pyridyl)amino)ethoxy-benzylidene)-2,4-thiazolidinedione by a similar procedure to that described in Example 1. 0458 1H NMR (DMSO-d6) 0459 2.9-3.4 (2H, complex); 3.1 (3H, s); 3.9 (2H, t); 4.1S (2H, t); 4.8 (1H, complex); 6.5-6.85 (2H, complex); 6.8 (2H, d); 7.2 (2H, d); 7.5 (1H, complex); 8.1 (1H, d); 12.05 (1H, broad s, exchanges with D2O).

EXAMPLE 31 0460 5-(4-2-(N-Methyl-N-(2-pyridyl)amino)ethoxybenzylidene)-2,4-thiazolidinedione 87

0461 The title compound (m.p. 177-9 C.) was obtained from 4-(2-(N-methyl-N-(2-pyridyl)amino)ethoxybenzaldehyde (3.2 g) and 2,4-thiazolidinedione (1.1 g) by a similar procedure to that described in Example 4. 0462 1H NMR (DMSO-D2) 0463 3.1 (3H, s); 3.9 (2H, t); 4.2 (2H, t); 6.4-7.5 (7H, complex); 7.7 (1H, s); 8.1 (1H, d)

EXAMPLE 32 0464 5-(4-f4-(N-Methyl-N-(2-benzoxazolyl)amino)butoxybenzylidene)-2,4-thiazolidinedione. 88

0465 The title compound (m.p. 168 C.) was prepared from 4-4-(N-methyl-N-(2-benzoxazolyl)amino)butoxybenzaldehyde (3.5 g) and 2,4-thiazolidinedione (1.4 g) by a similar procedure to that described in Example 4. 0466 1 NMR DMSO-d6 0467 1.70 (4H, complex); 3.10 (3H, s); 3.25 (1H, exchanges with D2O); 3.50 (2H, complex); 4.05 (2H, complex); 6.90-7.60 (8H, complex); 7.70 (1H, s).

EXAMPLE 33 0468 5-(4-4-(N-methyl-N-(2-benzoxazolyl)amino)butoxy-benzyl)-2,4-thiazolidinedione 89

0469 The title compound (m.p. 112 C., ethanol-hexane) was prepared from 5-(4-4-(N-methyl-N-(2-benzoxazolyl)-amino)butoxybenzylidene)-2,4-thiazolidinedione by a similar procedure to that described in Example 1. 0470 1H NMR CDCl3 0471 1.85 (4H, complex); 3.10 (1H, complex); 3.15 (3H,s); 3.40 (1H,dd); 3.60 (2H,t); 4.00 (2H,t); 4.50 (1H,dd); 6.80-7.40 (8H, complex); 9.30 (1H, br, exchanges with D2O).

EXAMPLE 34 0472 5-(4-2-(N-(2-Benzoxazolyl)aminoethoxybenzylidene)-2,4-thiazolidinedione 90

0473 The title compound (m.p. 242-5 C.) was prepared from 4-2-(N-(2-benzoxazolyl)amino)ethoxybenzaldehyde (5.18 g) and 2,4-thiazolidinedione (2.36 g) by a similar procedure to that described in Example 4. 0474 1H NMR DMSO-d6 0475 3.80 (2H,t); 4.35 (2H,t); 7.00-8.00 (9H, complex); 8.20 (1H, br, exchanges with D2O); 13.5 (1H, br, exchanges with D2O).

EXAMPLE 35 0476 5-(4-2-(N-(2-Benzoxazolyl)amino)ethoxybenzyl)-2, 4-thiazolidinedione 91

0477 The title compound (m.p. 202-3 C.; dichloromethane) was prepared from 5-(4-2-(N-(2-benzoxazolyl)amino)ethoxybenzylidene)-2,4-thiazolidinedione (6.1 g) by a similar procedure to that described in Example 1. 0478 1H NMR DMSO-d6 0479 3.10 (1H,dd); 3.30 (1H,dd) 3.70 (2H, complex); 4.15 (2H,t); 4.85 (1H,dd); 6.80-7.50 (8H, complex); 8.15 (1H, complex; exchanges with D2O); 12.00 (1H, br, exchanges with D2O).

EXAMPLE 36 0480 5-(4-2-(N-Isopropyl-N-(2-benzoxazolyl)amino)ethoxybenzyl)-2,4-thiazolidinedione. 92

0481 Sodium hydride (60% dispersion in mineral oil, 0.93 g) was added portionwise to a stirred solution of 5-(4-hydroxybenzyl)-2,4-thiazolidinedione (2.45 g in dry DMF (50 ml)) at room temperature under a nitrogen atmosphere. The mixture was stirred for 1 hour prior to the addition of a solution of 2-(N-isopropyl-N-(2-benzoxazolyl)aminoethanol methanesulphonyl ester (3.3 g) in dry DMF (60 ml). After stirring at room temperature for a further hour, the mixture was heated at 80 C. for 21 hours, then cooled, diluted with water (1l) and acidified to pH 6.5 with hydrochloric acid. The resulting suspension was extracted with ethyl acetate (2500 ml), and the combined ethyl acetate layers washed with water (31l), brine (1l), dried (MgSO4) and evaporated. The residual oil was chromatographed on silica gel with 1.5% methanol-dichloromethane as solvent to afford the title compound as a foam (m.p. 66 C.). 0482 1H NMR (CDCl3) 0483 1.35 (6H,d); 3.1 (1H, dd); 3.4 (1H, dd); 3.8 (2H,t); 4.15 (2H, complex); 4.35-4.65 (2H, complex); 6.85-7.4 (8H, complex); and 9.15 (1H, broad s,; exchanges with D2O). 0484 DEMONSTRATION OF EFFICACY OF COMPOUNDS 0485 Obese Mice, Oral Glucose Tolerance Test. 0486 C57bl/6 obese (ob/ob) mice were fed on powdered oxoid diet. After at least one week, the mice continued on a powdered oxoid diet or were fed powdered oxoid diet containing the test compound. After 8 days on the supplemented diet all of the mice were fasted for 5 hours prior to receiving an oral load of glucose (3 g/kg). Blood samples for glucose analysis were taken 0, 45, 90 and 135 minutes after glucose administration and the results appear below as the percentage reduction in area under the blood glucose curve where test compound treated groups are compared with the control groups. 7 mice were used for each treatment. 1LEVEL IN DIET% REDUCTION IN AREA(mol kg1 ofUNDER BLOOD GLUCOSEEXAMPLE NO:DIET)CURVE1100512300303103943003051004075047910058111003413100371510039171003419302221303324301525301927300562930032333002535100443610020

0487 Anti-Hypertensive Activity 0488 Eight month old female, spontaneously hypertensive rats were given test compound once each day for 15 days. Prior to the experiment and on days 8 and 15, the rats were fasted overnight from 5.00 pm and blood pressure was recorded the following morning, immediately prior to dosing and again 2h later. Food was returned after the 2h blood pressure reading. 0489 The results below were obtained using the compound of Example 3 as the test compound. 2Blood pressure (mm Hg)Treatment GroupTime0 hours2 hoursControlDay 0210 13Test Compound (30 mole/kg)Day 0210 13Test Compound (10 mole/kg)Day 0210 13ControlDay 8196 11195 12Test Compound (30 mole/kg)Day 8181 11*174 15**Test Compound (10 mole/kg)Day 8191 6185 12ControlDay 15208 12208 9Test Compound (30 mole/kg)Day 15178 18**170 13***Test Compound (10 mole/kg)Day 15198 17185 5***

0490 Significance of difference from control value at same timepoint: 0491 *p<0.05; **p<0.01; ***p<0.001. 0492 Toxicology 0493 No toxicological effects were indicated for any of the compounds of the invention in any of the abovementioned tests.