However poor bioavailability and rapid clearance are observed with these analogues, principally as a result of the chemical and metabolic stability of the acetal function present in these derivatives. One of the principal routes of metabolism of artemether, for example, involves oxidative dealkylkation to DHA, a compound associated with toxicity3 and short half-life. 4 Replacement of the oxygen at the C-10 position with carbon would be expected to produce compounds not only with greater hydrolytic stability, but also with a longer half-life and potentially lower toxicity. Consequently, several groups have developed synthetic and semi- synthetic approaches to C-10 carba analogues. 5-8 1.2 Statement of Invention A first aspect of the present invention, therefore, relates to antimalarial compounds of the following general formula: Beta-series <BR> <BR> (5) R=H (6) R = Me (7) R=CF 3 (8) R = OMe (9) R=F (10) R= Naphthyl Alpha-series <BR> <BR> <BR> <BR> <BR> (11) R=H<BR> <BR> <BR> (12) R = Me (13) R=CF 3 (14) R = OMe <BR> <BR> (I 5) R = F<BR> <BR> <BR> (16) R = Naphthyl (17) t-Bu A second aspect of the present invention, therefore, relates to a process of production of the above-specified antimalarial compounds via a TMSOTf/AgCI04 catalysed DHA-phenol derivative coupling reaction.

1.3 Summary of Invention This invention is concerned with the preparation of several, novel antimalarial phenoxy derivatives of dihydroartemisinin (DHA) that have been designed to prevent oxidative biotransformation to (DHA) in vivo. Thus, the compounds that have been designed, should be less neurotoxic and should have longer half-lives than the currently available derivatives. All of the compounds examined have potent antimalarial potency in vitro. Furthermore, the parent phenoxy derivative and thep-trifluoromethyl phenoxy derivative (7) demonstrated outstanding antimalarial activity in vivo against Plasmodium berghei in the mouse model.

1.4 Description of the Invention Several synthetic approaches have been investigated for the production of target C-10 derivatives.

One of the first approaches taken was to couple DHA with various phenols using boron trifluoride diethyl etherate catalysis. This method has been used by many researchers for DHA couplings to form first generation endoperoxides and it was therefore decided to use this route as our initial approach to the required derivatives. The method involved reacting 1 equivalent of DHA with 4 equivalents of the phenol in anhydrous ether at room temperature, in the presence of the BF3 etherate catalyst. In every case, the major product obtained in the reaction was the anhydro derivative in high yield. This suggests the involvement of an oxonium ion (Scheme 1) intermediate for this reaction. The oxonium ion, being a chemically reactive intermediate, could either react once formed with a phenol to give the phenyl ether, or by loss of a proton give the byproduct, anhydroartemisinin. Both reactions compete for the oxonium ion.

Indeed Lin et al comments that rate of reaction with a sterically hindered secondary or tertiary alcohol is slower than a less hindered primary alcool. As a result formation of the by-product became the predominant reaction. 9 As phenol is effectively a tertiary alcool, it seems likely that the poor yields of product obtained are as a result of this process.

The compounds prepared using BF3 Et20 are shown in Table 1. For the majority of the compounds obtained, the ß isomer predominated, as shown by the small coupling constants between H-9 and H-10 (J=3-4.0Hz). Major -Route : 0/ b., BF3. Et20 AHA b., T HI2 OH'I DHA R = H, Cl, F, tBu, OMe Oxonium Intermediate Minou Route dAr Scheme 1 Synthesis of Phenoxy Derivatives using BF3. Et20 as Lewis Acid R Yield (%) Isomer ßH10 ci ß F 311(3 Ome 18 ß TBu 19 a Table 1 Yields and Stereochemistry of Phenoxy derivatives obtained from DHA using BF3.Et20 The low yields led us to examine different methods of forming the C-10 phenoxy derivatives. An idea briefly considered was the Mitsunobu reaction. Classically, the Mitsunobu reaction is used to synthesise esters from a carboxylic acid and an alcohol in the presence of triphenylphosphine and an azodicarboxylate (typically the diisopropyl or diethyl derivative). l° 1l We believed that we could use a modification of this process to allow the coupling of DHA to our phenols in the presence of diethyl azodicarboxylate and triphenylphosphine. However, for the coupling of tert-butyl phenol, the reaction occurred in very poor yield, 27%. In addition the compound proved difficult to purify due to the presence of triphenylphosphine oxide. The product was isolated as a mixture of a and P isomers. NMR studies revealed that the 0 isomer was the major isomer with a diastereomeric ratio of 12.5: 1 in favour of the ß isomer. Due to the problems of isolation of product and poor yield it was decided to consider a different route.

The dihydroartemisinin lactol can be recognised as a pyranose sugar with a free anomeric hydroxyl group. 12 There are many papers detailing reactions of glycosides, including C-C bond formation at the anomeric site.' Recently, studies by Suzuki have been carried out in investigate the O to C glycoside rearrangment of phenoxy glycosides. l5 Usually the phenoxy derivative is prepared in situ and allowed to rearrange into the corresponding C-aryl glycoside.

Such two stage reactions proceed in one pot in the presence of Lewis acids. Different Lewis acid promoters have been used, including BF3 etherate, SnC14 and Cp2HfCl2-AgClO4 with varying success. Suzuki noted that the anomeric composition was largely (3, with a small amount of a anomer. This stereochemical aspect was explained by the thermodynamic equilibration to the more stable (3 anomer from the initially formed anomeric mixture.

In 1992, Toshima discovered the efficient ß-stereoselective C-aryl glycosidation of 1-0- methylsugars by the novel use of a TMSOTf-AgC104 catalyst system.'6 This procedure gives excellent yields and diastereoselectivity in favour of the (3-isomer, by rearrangement of the pre- formed phenoxy glycoside as shown (Scheme 2, A). Such promising results led us to try the use of TMSOTf-AgC104 catalysis in our DHA-phenol coupling reactions. This approach involves dissolving 1 equivalent of DHA, approximately 2 equivalents of the desired phenol and one-fifth 0 equivalents of silver perchlorate in anhydrous dichloromethane, under nitrogen at-78 C. The TMSOTf is usually added to the reaction mixture last. In every case, the reaction provided excellent yields with good diastereoselectivity in favour of the beta isomers. Notably, only minor quantities of9, 10-dehydrodeoxoartemisinin were observed (Scheme 2, B). FA Ma Step 2 M TMSOTf/AgC 104 n (OR) n (OR n (OR)- \ X OAc,OMe \t Anomer B TMSOTF AgC 104 Rearrangetnent O OH 0"Jk. OU DHA R = H, Cl, F, tBu, OMe 1))) h R 60-85 % Yield ß-Isomer Favoured cheme 2 Route A, O to C TMSOTf/AgCl04 catalysed C-Aryl Glycoside Synthesis and Route B, TMSOTU AgCl04 Catalysed Synthesis of Dihydroartemisinin Derivatives Notably, no O to C-aryl glycoside rearrangment was noted for any of the phenoxy derivatives obtained in contrast to the situation depicted in route A. R Combined Ratio Yield (%) ß: a H 58 4: 1 5:1Me84 8:1CF368 Ome 73 4 : 1 F 60 3: 1 5:1Cl62 Naphthyl :15 Table 2 Yields of Phenoxy derivatives using TMSOTf/AgCl04 As can be seen from the table, (Table 2), the increase in yield upon using the new system was dramatic. Noticeably, when R = OMe, the yield increased by 55% (the yield was only 18% using BF3. Et20 catalysis). The best diastereoselectivity was observed when R = CF3. There is no obvious explanation for the success of this reaction. It may be that under these conditions the oxonium ion is stabilised and therefore less likely form the by-product. Alternatively these conditions may catalyse slow oxonium ion formation. Hence at any one time there are larger quantities of nucleophile available to react with the intermediate oxonium species.

All of the compounds were obtained as crystalline solids. The diastereoselectivity ratios were calculated from NMR data. As mentioned previously, the isomer obtained could be deduced from the coupling constant between 9-H and 10-H. Where J = 3-4Hz, the isomer is ß and when J =-9 Hz, the isomer is a.

The following examples illustrate the invention; 1.5 Examples 10 P- (Phenyloxv') dihydroartemisinin (5) and 10 a- (phenyoxy) dihydroartemisinin (I I To a stirred solution of dihydroartemisinin, (1.0 g, 3.54 mmol), in dichloromethane, (25 ml), was added phenol, (1.0 g, 10.5 mmol) and silver perchlorate, (0.15 g, 0.72 mmol). The resulting solution was cooled to -78°C, (CO2 / acetone) and trimethylsilyl triflate, (1.0 ml, 5.00 mmol), added. The reaction was allowed to stir for 1 hour. After this time the reaction was quenched with triethylamine, (1.5 ml), and allowed to warm to room temperature. The reaction was filtered, and the solvent removed in vacuo. Purification by column chromatography gave the required product as the ß and a isomers, (0.74 g, 58%).

Data for the p-isomer; mpt, 104-106 °C ; [a] D + 204°, (c, 1.0, CHCl3) ; vmax (nujol mull)/cm-, 2926 (CH), 1463,1193,875 (O-O), 832 (O-O); 8H (300 MHz, CDC13), 0.96 (3H, d, J 6.0, Me at C-9), 1.13 (3H, d, J 7. 4, Me at C-6), 1.44 (3H, s, Me at C-3), 1.23-2.07 (1OH, m), 2. 39 (1H, dt), 2.81 (1H, m), 5.50 (2H, d), 6.99 (1H, t, J 7.9, I x aromatic), 7.22 (2H, d, J 8.8,2 x aromatic), 7.29 (2H, t, J 8.8,2 x aromatic); 5c (75 MHz, CDC13), 157,129,122,116,104,100,88,81,52, 44,37,36,34,31,26,25,24,20,12; m/z (EI), 361 (M+, 85%), 267 (M+-OPh, 33%), 221 (25%).

Data for a-isomer; mpt, 143-145 °C; [a] D-54.5°, (c, 1.0, CHCl3) ; vmax (nujol mull)/cmi', 2925 (CH), 1040,881 (O-O), 825 (O-O); 8H (300 MHz, CDC13), 0.97 (3H, d, J 1.8, Me at C-9), 0.99 (3H, d, J 3.2, Me at C-6), 1.43 (3H, s, Me at C-3), 1.26-2.10 (10H, m), 2.42 (IH, dt), 2.73 (IH, m), 5.05 (IH, d, J 9.5), 5.49 (1H, s), 7.00 (1H, t, J 7.1, I x aromatic), 7.11 (2H, d, J 5.8,2 x aromatic), 7.25 (2H, t, J 4. 4,2 x aromatic); #c (75 MHz, CDCl3), 145,129,122,117,104.5,100, 99,91,52,45,37,36,33,26,25,22,20,12.5; m/z (CI, NH3), 378 ( [M + NH4]+, 44%), 332 (90%), 301 ( [M + NH4]+ - Ph, 5%), 221 (100%); Found [M + NH4] 378.22777, C2lH32NO5 requires 378.22805. dihydroartemisinin(6)and10ß-[(p-{methyl}phenyl)oxy]10α-[(p -{Methyl}phenyl)oxy] dihydroartemisinin(12) To a stirred solution of dihydroartemisinin, (1.0 g, 3.54 mmol), in dichloromethane, (25 ml), was added p-cresol, (1.0 g, 9.25 mmol) and silver perchlorate, (0.15 g, 0.72 mmol). The reaction was cooled to-78°C, (COz/acetone) and trimethylsilyl triflate, (1.0 ml, 5.00 mmol) added. The reaction was allowed to stir for 1 hour. After this time the reaction was quenched with triethylamine, (1.5 ml) and warmed to room temperature. The reaction was filtered and the solvent removed in vacuo. Purification by column chromatography then gave the required product as the (3 and a-isomers, (1.14 g, 84%).

Data for (3-isomer; mpt 78-80°C; [a] D + 175°, (c 1.0, CHCl3) ; Vmax (nujol mull)/cm, 2925 (CH), 1509,1226,1036,979,959,876 (O-O); 5H (300 MHz, CDCl3), 0.95 (3H, d, J 6.0, Me at C-9), 0.99 (3H, d, J 5.7, Me at C-6), 1.40 (3H, s, Me at C-3), 1.20-2.07 (IOH, m), 2.27 (3H, s, Me), 2.37 (1H, dt), 2.78 (1H, m), 5.43 (1H, d, J 3.4), 5.5 (IH, s), 7.01 (4H, m, aromatic); 8c (75 MHz, CDC13), 156,131,129,117,104,100,88,81,77,60,53,44.5,37,36,35,31,26,2 4,21, 20,14,13; m/z (FAB), 375 ( [M + H]+, 45%), 329 (100%), 267 ( [M + H] +-OC6H4Me, 22%).

Data for a-isomer; mpt 160-162°C ; [a] D-59°, (c 1.0, CHCl3) ; Observed, C 70.62%, H 8.11%, C22H30O5 requires C 70.55%, H 8.09%; vmax (nujol mull)/cm, 2925 (CH), 1509,1225,1038, 878 (O-O), 818 (O-O); 5H (300 MHz, CDC13), 0.97 (6H, d, J4.7, Me at C-9 and C-6), 1.42 (3H, s, Me at C-3), 1.23-2.07 (1OH, m), 2.28 (3H, s, Me), 2.40 (1H, dt), 2.71 (1H, m), 4.98 (1H, d, J 9.0), 5.46 (1H, s), 7.05 (4H, m, aromatic); 8c (75 MHz, CDCl3), 156,131.5,130,117,104,99, 91,80,52,45,37,36,34,33,26,25,22,20.5,20,12.5; m/z (FAB), 375 ( [M + H] , 18%), 329 (100%), 267 ( [M + H] +-OC6H4Me, 30%). <BR> <BR> <BR> <BR> <BR> <BR> and10ß-[(p-{trifluoro}phenyl)oxy]10α-[(p-{Trifluoro}phenyl )oxy]dihydroartemisinin(7) dihydroartemisinin (13) To a stirred solution of dihydroartemisinin, (1.0 g, 3.52 mmol), in dichloromethane, (25 ml), was added trifluoro-p-cresol, (1.0 g, 6.20 mmol) and silver perchlorate, (0.15 g, 0.72 mmol). The reaction was cooled to-78°C, (CO2/acetone) and trimethylsilyl triflate, (1 ml, 5.00 mmol), added. The reaction was allowed to stir for 1 hour. After this time the reaction was quenched with triethylamine, (1.5 ml) and allowed to warm to room temperature. The reaction was filtered and the solvent removed in vacuo. Purification by column chromatography then gave the required product as the ß and a-isomers, (1.03 g, 68%).

Data for the ß-isomer; mpt 141-143°C ; [a] D + 167°, (c 1.0, CHCl3) ; Observed, C 61.86%, H 6.41%, C22H2705F3 requires C 61.67%, H 6.35%; vmax (nujol mull)/cm), 2925 (CH), 1461, 1377,1328,1240,1151,1108,981,876 (0-0); 8H (300 MHz, CDC13), 0.95 (3H, d, J 6.0, Me at C-9), 1.02 (3H, d, J 8.0, Me at C-6), 1.43 (3H, s, Me at C-3), 1.21-2.05 (10H, m), 2.36 (1H, dt), 2.86 (1H, m), 5.45 (IH, s), 5.57 (IH, d, J 3.0), 7.20 (2H, d, J 8.0,2 x aromatic), 7.55 (2H, d, J 8.0,2 x aromatic); 8c (75 MHz, CDC13), 160,127,117,104,100,88,80,52.5,44,37,36,35, 31,26,25,24,20,13; m/z (CI), 429 ( [M + H] +, 64%), 411 ( [M + H] +-F, 34%), 289 (74%), 221 (18%) ; Found [M + H] + 429.18818, C22H2805F3 requires 429.18888.

Data for the a-isomer; mpt 161-163°C; [a] D-39. 5°, (c 1.0, CHCl3) ; v,,,,, (nujol mull)/crri', 2926 (CH), 1462,1120,1037,879 (0-0), 838 (0-0); 8H (300 MHz, CDCI3), 0.98 (6H, d, J 5.0, Me at C-9 and C-6), 1.50 (3H, s, Me at C-3), 1.26-2.09 (10H, m), 2.41 (1H, dt, J 4.0), 2.78 (1H, m), 5.10 (1H, d, J 9.0), 5. 51 (1H, s), 7.17 (2H, d, J 8.0,2 x aromatic), 7.54 (2H, d, J 9.0,2 x aromatic); 8c (75 MHz, CDCl3), 127,117,105,98.5,91,80,52,45,37,36,34,32,26,22,24, 20,12; m/z (CI), 429 ( [M + H]+, 26%), 383 (85%), 289 (100%), 221 (25%), 43 (100%). <BR> <BR> <BR> <BR> <BR> <BR> <BR> and10α-[(p-{methoxy}phenyl)oxy]10ß-[(p-{Methoxy}phenyl)oxy ]dihydroartemisinin(8) dihydroartemisinin(14 ! To a stirred solution of dihydroartemisinin, (1.0 g, 3.52 mmol), in dichloromethane, (25 ml), was added 4-methoxyphenol, (1.0 g, 8.06 mmol) and silver perchlorate, (0.15 g, 0.72 mmol). The reaction was cooled to-78°C, (C02/acetone) and trimethylsilyl triflate, (1 ml, 5.00 mmol), added. The reaction was allowed to stir for I hour. After this time the reaction was quenched with triethylamine, (1.5 ml) and allowed to warm to room temperature. The reaction was filtered and the solvent removed in vacuo. Purification by column chromatography then gave the required product as the 0 and a-isomers, (1.17 g, 85%).

Data for the ß-isomer; mpt 118-120°C. [a] D + 141.1°, (c 1.0, CHC13) ; Observed C 67.45%, H 7.77%, C22H3006 requires C 67.67% H 7.74%; vmax (nujol mull)/cm, 2990 (CH), 1421,1262, 895 (O-O); #H (300 MHz, CDCl3), 0.95 (3H, d, J 3.6, Me at C-9), 1.02 (3H, d, J 7.2, Me at C- 6), 1.43 (3H, s, Me at C-3), 1.21-2.07 (1OH, m), 2. 38 (1H, dt), 2.78 (1H, m), 3.76 (3H, s, OMe), 5. 37 (1H, d, J 3.3), 5.53 (1H, s), 6.83 (2H, m, 2 x aromatic), 7.03 (2H, m, 2 x aromatic); 8c (75 MHz, CDCl3), 155,152,118,115,104,102,88,81,56,53,44,37,36,35,31,26,25,24, 20, 13; m/z (CI, NH3), 408 ( [M + NH4], 7%), 373 (24%), 348 (51%), 345 (100%), 221 (100%); Found, [M + NH4] 408.23798 C22H34NO6 requires 408.23861.

Data for the a-isomer; mpt 147-149°C. [α]D - 43.5°, (c 1.0, CHCl3); Observed C 67.40%, H 7.69%, C22H30O6 requires C 67.67% H 7. 74%; Vmax (nujol mull)/cm~, 2934 (CH), 1468,1423, 1379,1224,1131,1029,879 (O-O), 825 (O-O); 5H (300 MHz, CDC13), 0.96 (3H, d, J4.86, Me at C-9), 1.02 (3H, d, J 13.5, Me at C-6), 1.42 (3H, s, Me at C-3), 1.22-2.07 (10H, m), 2.40 (1H, dt), 2.70 (1H, m), 3.76 (3H, s, OMe), 4.92 (IH, d, J 9.3), 5.44 (1H, s), 6.80 (2H, m, 2 x aromatic), 7.08 (2H, m, 2 x aromatic); 8c (75 MHz, CDCl3), 155,152,118.5,114.5,104,100, 91,80,56,52,45,37,36,34,33,26,25,22,20,12.5; m/z (CI, NH3), 390 ( [M + H] +, 16%), 221 (28%), 124 (80%).

10ß-[(p-{Fluoro}phenyl)oxy] dihydroartemisinin (9) and 10a-[(p-fluoro}pheny!oxy] dihydroartemisinin(15) To a stirred solution of dihydroartemisinin, (0.10 g, 0.35 mmol), in dichloromethane, (3 ml), was added 4-fluorophenol, (0.10 g, 0.89 mmol) and silver perchlorate, (0.015 g, 0.073 mmol). The reaction was cooled to-78°C, (CO2/acetone) and trimethylsilyl triflate, (0.1 ml, 0.5 mmol), added. The reaction was allowed to stir for I hour. After this time the reaction was quenched with triethylamine, (0.5 ml) and allowed to warm to room temperature. The reaction was filtered and the solvent removed in vacuo. Purification by column chromatography then gave the required product as the ß isomer, (0.2 g, 60%), mpt 75-77°C. [a] D + 186°, (c 1.0, CHCl3) ; Observed, C 66.74%, H 7.54%, C2lH2705F requires C 66.62%, H 7.21%; vn"", (nujol mull)/cm~', 2932 (CH), 1503,1378,1139,1121,1095,877 (O-O), 832 (O-O); OH (300 MHz, CDCl3), 0.97 (3H, d, J 6.0, Me at C-9), 1.02 (3H, d, J 7.2, Me at C-6), 1.42 (3H, s, Me at C-3), 1.21-2.07 (IOH, m), 2. 38 (1H, dt), 2.79 (1H, m), 5.51 (1H, s), 6.9-7.1 (4H, m, aromatic); #c (75 MHz, CDCl3), 160,156.5,154,118,116,104,101,86,81,52.5,44,37,36, 35,31,26,25,20,13; m/z (EI), 379 (M+, 39%), 361 (M+-F, 61%), 333 (69%), 289 (74%), 221 (18%). <BR> <BR> <BR> <BR> <BR> <BR> <P>(10)and10ß-[(naphthyl)oxy]dihydroartemisinin(16).1 0α-[(Naphthyl)oxy]dihydroartemisinin To a stirred solution of dihydroartemisinin, (2.0 g, 7.04 mmol), in dichloromethane, (50 ml), was added 2-naphthol, (2.0 g, 13.9 mmol) and silver perchlorate, (0.30 g, 1.45 mmol). The reaction was cooled to-78°C, (CO2/acetone) and trimethylsilyl triflate, (2 ml, 10 mmol), added. The reaction was allowed to stir for I hour. After this time the reaction was quenched with triethylamine, (5 ml) and allowed to warm to room temperature. The reaction was filtered and the solvent removed in vacuo. Purification by column chromatography then gave the required product as the ß and a-isomers, (2.44 g, 84%).

Data for the p-isomer; mpt 138-140 C. [a] D + 240°, (c 1.0, CHCl3) ; Observed, C 72.92%, H 7. 41%, C25H30O5 requires C 73.15%, H v (nujo ! mull)/cm'\ 2926 (CH), 1464,1211, 977,839 (O-O); on (300 MHz, CDC13), 0.97 (3H, d, J 6.0, Me at C-9), 1.06 (3H, d, J 8.0, Me at C-6), 1.46 (3H, s, Me at C-3), 1.23-2.12 (IOH, m), 2.40 (IH, dt), 2.86 (1H, m), 5.55 (1H, s), 5.66 (1H, d, J 3.0), 7.24 (2H, d, J 9.0,2 x aromatic), 7.40 (3H, m, 3 x aromatic), 7. 56 (1H, s, 1 x aromatic), 7.75 (1H, d, J 9.0, I x aromatic); 5c (75 MHz, CDC13), 155,135,129,127,126,124, 119,111,100,88,81,53,44.5,37,36,35,31,26,25,24,20,13; m/z (EI), 410 (M+, 22%), 364 (100%), 221 (25%), 163 (61%), 144 (100%), 43 (72%); Found, M+ 410.20913, C25H3005 requires, 410.20932.

Data for the a-isomer; mpt 148-150 C. [a] D + 16°, (c 1.0, CHCl3); vmax (nujol mull)/cm-1, 2926 (CH), 1465,1377,10381,879 (O-O), 839 (O-O); 8H (300 MHz, CDC13), 1.00 (3H, d, J 7.2, Me at C-9), 1.06 (3H, d, J 12.9, Me at C-6), 1.56 (3H, s, Me at C-3), 1.26-2.08 (10H, m), 2.43 (1H, dt), 2.78 (1H, m), 5.33 (1H, d, J 9. 3 0), 5.58 (1H, s), 7.40 (5H, m, 5 x aromatic), 7.75 (2H, m, 2 x aromatic); 8c (75 MHz, CDCl3), 80,52,45,37,36,34, 32.5,26,22,20,12.5; m/z (EI), 410 (M+, 100%), 364 (97%), 346 (82%), 321 (38%), 304 (54%), 221 (24%), 163 (93%), 144 (100%), 115 (58%), 43 (87%); Found, M+ 410.20913, 410.20932.C25H30O5requires, 1 Oa-[(p-f t-Butyl} phenvl ! oxyjdihydroartemisinin.

To a stirred solution of dihydroartemisinin, (0.3 g, 1.06 mmol), in diethyl ether, (50 ml), was added 4-tert-butylphenol, (0.63 g, 4.22 mmol) and boron trifluoride etherate, (0.25 ml) and the reaction allowed to stir for 48 hours. After this time the reaction was quenched with water, the organic layer removed and the aqueous layer extracted with ethyl acetate, (3 x 40 ml). The organic layers were combined, washed with 5% sodium bicarbonate solution (3 x 40 ml), washed with water, (3 x 40 ml), dried, (MgSO), filtered and the solvent removed in vacuo to give the crude product as a pale liquid. Purification of this by column chromatography eluting with 95: 5 hexane to ethyl acetate, then gave the required product as the a-isomer, (0.087 g, 19%), mpt 143-145°C. [a] D + 85°, (c 1.0, CHCl3) ; Observed, C 72.33%, H 8.84%, C25H36O5 requires C 72.08%, H vmax (nujol mull)/cm-1, 2990 (CH), 1420,1256,894 (0-0); aH (300 MHz, CDCI3), 0.96 (3H, d, J 2.8 Me at C-9), 0.97 (3H, d, J 1.8, Me at C-6), 1.29 (9H, s, t-Bu), 1.54 (3H, s, Me at C-3), 1.26-2.07 (10H, m), (IH, m), 5.03 (1H, d, J9.0), 5.47 (1H, s), 6.88 (2H, d, J 4.5,2 x aromatic), 7.28 (2H, d, J 6.9,2 x aromatic); 5c (75 MHz, CDCl3), 126,116, 104,99,91,80,52,45,38,36,34,33,31.5,26,25,24,22,20,12.5; m/z (EI), 416 (M+, 16%), 371 (100%), 279 (M+ - OC6H4C(CH3)3).

1.6 Biological Properties of the Invention The antimalarial activity of the C-10 phenoxy derivatives were tested in vitro, against the K-1 chloroquine resistant strain of P. falciparum, (Tables 3 and 4). R ß-isomer IC50 (nM) Std. Err Artemether 3. 00 1.88 H 3. 66 0. 11 Me 3. 92 0. 08 CF3 5. 29 0.02 Ome F 4. 58 0. 04 Naphthyl 8. 89 0.05 Table 3, Results for the ß-isomers against the K1 chloroquine resistant strain. R a-isomer IC50 (nM) Std. Err H 2. 97 0.02 Me 3. 18 0. 05 CF3 4. 62 0.06 Ome 3. 86 0.24 1.01F5.70 Tbu S. 56 0. 09 Naphthyl 2. 88 0.04 Table 4, Results for the a-isomers against the K1 chloroquine resistant strain.

Comparing ß and a isomers with 0-artemether against the Kl chloroquine resistant strain there are several compounds which exhibit comparable if not more potent antimalarial activity. The phenyl and fused phenyl a-isomers, for instance, are slightly more potent than artemether. The derivatives tested in Tables 3 and 4 were further tested against the chloroquine sensitive HB3 strain of P. falciparum, Tables 5 and 6. R-isomer IC50 (nM) Std. Err Artemether 3. 42 1. 14 H 3. 24 0. 05 Me 3. 24 0. 16 CF3 3. 90 0.07 F 2. 88 0. 21 Naphthyl 7.06 0.04 Table 5, Results for the (3-isomers against the chloroquine sensitive HB3 strain R a-isomer IC50 (nM) Std. Err. H 2. 61 0. 31 Me 2. 87 0.10 CF3 3. 42 0. 05 OMe 3. 32 0. 14 F 4. 04 0. 03 TBu 3. 72 0. 22 0.0360Naphthyl2.8860 Table 6, Results for the a-isomers against the chloroquine sensitive HB3 strain Of the compounds tested against the HB3 strain of P. falciparum, the most potent (3-isomers, were the phenyl, 4-methylphenyl and 4-fluorophenyl DHA derivatives. These were all more potent than artemether. In the a-series, the phenyl, 4-methylphenyl, 4-methoxyphenyl and fused phenyl derivatives of DHA were all more potent than artemether. The 4-trifluoromethylphenyl ether, was of comparable activity to artemether.

Based on the excellent stereoselectivity obtained for the para-trifluoromethyl derivative, this compound along with the parent phenyl substituted derivative, were selected for in vivo biological evaluation against Plasmodium berghei in the mouse model.

1.7 Biological Testing Protocols In vitro Two strains of Plasmodium, falciparum from Thailand were used in this study: a) the uncloned K 1 strain which is known to be chloroquine resistant and b) the cloned T9.96 strain which is sensitive to all antimalarials.

Parasites were maintained in continuous culture using a method derived from that of Jensen and Trager. 18 Cultures were maintained in culture flasks containing human erythrocytes (2-5 %) with parasitaemia ranging from 0.1-10% suspended in RPMI 1640 medium supplemented with 25mM HEPES buffer, 32mM NaHCO3 and 10% human serum (complete medium). Cultures were gassed with a mixture of 3% 02,4% C02 and 93% N2.

Antimalarial activity was assessed using an adaptation of the 48 hour sensitivity assay of <BR> <BR> <BR> t9 Q<BR> <BR> Desjardins et al using [3H]-hypoxanthine incorporation as an assessment of parasite growth.

Stock drug solutions were dissolved in 100% ethanol and diluted to an appropriate concentration with complete medium (final concentrations contained less than 1% ethanol). Assays were performed in sterile 96 well microlitre plates, each well containing IOOIIL of medium which was seeded with 10LL of a parasitised red blood cell mixture to give a resulting initial parasitaemia of 1% with a 5% haematocrit. Control wells (which constituted 100% parasite growth) consisted of the above, with the omission of the drug.

After 24h incubation at 37°C, 0. 5nCi of Hypoxanthine was added to each well. After a further 24 hours incubation the cells were harvested onto filter mats, dried overnight, placed in scintillation vials with 4mL of scintillation fluid and counted on a liquid scintillation counter.

IC50 values were calculated by interpolation of the probit transformation of the log-dose response curve. Each compound was tested against both strains to ensure reproducibility of the results.

In vivo The standard 4-day test was used to obtain ED50 or IC50 values. 12 The values obtained are shown in Figure 1.

Whereas the invention has principally been described in relation to the treatment of malaria, compounds of the invention may also find a use for other purposes and particularly in the treatment of cancer and proliferative disorders (eg. psoriasis).

Antimalarial trioxanes based on artemisinin and arteether have previously been shown to possess anti-proliferative and anti-tumour activities in vitro, as evidenced by their effects on the growth of normal murine keratinocytes and a range of cancer cell lines respectively and, accordingly, compounds of the invention may be used in this context.

1.8 References (1) W. Asawanahasakda et al, Am. Soc. Micro., 1994,1854 (2) S. R. Meshnick et al, Parasitology Today, 1996,12,79 (3) M. Jung et al, Bioorg &Med. Chem. Lett., 1998,8,1003 (4) X-D Luo, Med. Res. Rev., 1987,7,29 (5) R. K. Haynes et al, Synlett, 1992,481 (6) H. O'Dowd et al, Tetrahed., 1999,55,3625 (7) S. H. Woo et al, Tet. Lett., 1998,39,1533 (8) Y-M Pu et al, J. Med. Chem, 1995,38,613 (9) Ai. Lin et al, J. Med. Chem., 1989,32,1249 (10) M. Varasi et al) J. O. C., 1987,52,4235 (11) D. L. Hughes et al, J. A. C. S., 1988,110,6487 (12) G. H. Posner et al, Tet. Letts., 1998,39,1533 (13) K. Suzuki et al, J. A. C. S., 1994,116,1004 (14) M. Postema, Tetrahedron, 1992,48,8545 (15) K. Suzuki etal, Tet. Letts., 1990,31,4624 (16) K. Toshima et al, Tet. Letts., 1992, 33,2175 (17) W. Peters Ann.Trop.Med.Parasitol.1993,87,1al (18) J. B. Jensen J. Parasitol., 1977,63,883 (19) R. E. Desjardins, Antimicrob. Agents. Chemother., 1979,16,710 (20) G. H. Posner et al, Bioorg. & Med. Chem., 1997,1257