WO2000004025A1 - Antiparasitic artemisinin derivatives (endoperoxides) - Google Patents

Abstract

This invention relates to the use of certain C-9 substituted derivatives of artemisinin of general formula (I) or a salt thereof in the treatment and/or prophylaxis of dieseases caused by infection with a parasite, certain novel C-9 substituted derivatives of artemisinin, processes for their preparation and pharmaceutical compositions containing such C-9 substituted derivatives. The compounds are particularly effective in the treatment of malaria, neosporosis and coccidiosis.

Description

ANTIPARASITIC ARTEMISININ DERIVATIVES (ENDOPEROXIDES)

This invention relates to the use of certain C-9 substituted derivatives of artemisinin in the treatment and/or prophylaxis of diseases caused by infection with a parasite, certain novel C-9 substituted derivatives of artemisinin, processes for their preparation and pharmaceutical compositions containing such C-9 substituted derivatives.

Malaria is the most important human parasitic disease in the world today. Approximately 270 million people throughout the world are infected with malaria, with about 2 million dying each year. The ability of parasites to produce a complex survival mechanism by expressing variant antigens on the surface of infected erythrocytes makes it possible for the parasites to escape from the destructive action of the host immune response against these antigens. In addition, the increasing rate of malaria infection is due to the spread of chloroquine-resistant strains of Plasmodium falciparum and the other multi-drug resistant strains. In the field of animal health, parasitic diseases are a major problem, especially those diseases which are functionally related to malaria. For instance, neosporosis is a term used to describe diseases caused by parasites of the species Neospora, especially Neospora caninum, in animals. Neospora infections are known to occur in dogs, cattle, sheep, goats and horses.

The final host for Neospora spp . , including Neospora caninum, is unknown and, in addition, the complete cycle of development of the parasite is not understood. The asexual phases of reproduction, known as schizogony, and the behaviour of the unicellular tachyzoite/bradyzoite stage have been clarified, however. Tachyzoites are infectious unicellular parasite stages of about 3-7 x 1-5 mm in size formed after mtracellular reproduction termed endodyogeny. Reproduction via tachyzoites takes place preferentially m organelles such as muscle or nerve cells. Pathological symptoms invoked after an infection are associated mainly m those tissues.

Some five to six weeks after natural infection- m a dog, symptoms of the disease are hypersensitivity caused by inflammation of neuronal cells and increasing tendency to hyperextension of the hind legs. Histopathological lesions are apparent m the nervous system, preferentially m the brain and spinal cord. Extensive non-suppurative inflammations, glial excrescences and perivascular infiltrations of mononuclear cells (macrophages , lymphocytes, plasma cells) dominate, and are also partly apparent m eosmophils and neutrophils. In the muscular system, macroscopically observable necroses and degenerative changes appear. Apart from the more or less strongly developed atrophy, long pale longitudinal stripes are evident.

In California and Australia, Neospora caninum infections appear to be the main cause for abortion m cattle. Symptoms of the disease m cattle are similar to those m the dog. Atax a is apparent, joint reflexes are weakened and pareses at the hmd legs, partly in all four legs, can be observed. The histological picture is similar to that of the dog; mainly non-suppurative meningitis and myelitis.

Data on m vivo activity of compounds suitable against neosporosis are rare because adequate m vivo test systems still have to be developed Sulfadiazm (administered via drinking water) is effective m experimentally infected mice, only if the treatment was prophylactic, that is, the treatment was started before infection In dogs, treatment with sulfadiazm and clindamycm is only successful if it is started early, that is, at the appearance of first clinical symptoms as a result of neuronal inflammation.

Coccidiosis, an infection of the small intestine, is relatively rarely diagnosed in humans, where it is caused by Isospora belli. However, humans are also the final host of at least two cyst -forming coccidial species (Sarcocystis suihominis and S. bovihomlnis) . Consumption of raw or inadequately cooked pork or beef containing such cysts can lead to severe diarrhoea, the cause of which is probably seldom diagnosed correctly. Coccidia (phylum Apicomplexa, suborder Eimeriina) are one of the most successful groups of parasitic protozoans, having conquered virtually every class of Metazoa. The ones that are of particular importance for man are the 60-100 species which parasitise domestic animals and which in some instances can cause very severe losses, especially in poultry, although also in lambs, calves, piglets, rabbits and other animals (see Table A) .

Table A: Causatives of intestinal coccidiosis m domestic animals

* regarding to Pe ler y 1974 , Ec ert et a , 1995 , Lev ne and Ivens (1970) and Mehlhorn 1988)

Most of the pathogenic species are strictly host- specific. They have a complex life cycle with two asexual reproduction phases (schizogony or merogony, and sporogony) and a sexual development phase (gametogony) In view of the major importance of coccidiosis, numerous reviews are available, for instance, by Davies et al (1963) , Hammond and Long (1973), Long (1982, 1990), and Pellerdy (1974). The economically important species sometimes differ very considerably in their sensitivity to medicinal active ingredients. The sensitivity of the different developmental stages to medicinal agents also varies enormously.

As far as the use of drugs is concerned, prophylaxis is the main approach in poultry, in which symptoms do not appear until the phase of increased morbidity, and therapy is the principal strategy in mammals (McDougald 1982) . Polyether antibiotics and sulfonamides , among other drugs, are currently used for such treatment and prophylaxis. However, drug- resistant strains of Eimeria have emerged and drug- resistance is now a serious problem. New drugs are therefore urgently required. Given the multiplicity of pathogens and hosts, there is no "ideal model" for identifying and testing anticoccidial agents. For example, most of the many substances used for preventing coccidiosis in poultry are insufficiently effective or even completely ineffective against mammalian coccidia (Haberkorn and Mundt ; 1989; Haberkorn 1996) . Numerous works and sets of instructions have been published on testing of active ingredients in animals for anticoccidial efficacy, for immunisation, etc. One particularly important and comprehensive example is the survey of current methods published by Eckert et al . (1995a) .

The compound artemisinin, also known as qinghaosu (1), is a tetracyclic 1 , 2 , 4-trioxane occurring in Artemisia annua . Artemisinin and its derivatives dihydroartemisinin (2), artemether (3) and sodium artesunate (4) have been used for the treatment of malaria .

Artemisinm 1 Dihydroat emtsmin 2 Λrle et cr 3 Sodium Artesunate <

Different modes of action have been proposed by various groups to account for the action of artemisinm and its derivatives m treating malaria (Posner et al . , J. Am . Chem . Soc .1996 , 118 , 3537_/Posner et al . , J. Am . Chem . Soc .1995 , 117, 5885 /Posner et al . , J. Med . Chem.1995, 38, 2273 ) . However, irrespective of actual mode of action, all current derivatives suffer from poor oral bioavailability and poor stability (Meshnick et al . , Parasi tology Today 1996 , 12, 79) , especially the 'first generation' ethers and esters artemether and sodium artesunate obtained from dihydroartemismm Extensive chemical studies carried out on artemisinm and derivatives indicate that a cause of instability is the facile opening of the tπoxane moiety in artemisinm itself, or in the metabolite common to all currently used derivatives artemether, arteether and artesunate, namely dihydroartemismm. Ring opening will provide the free hydroperoxide, which is susceptible to reduction. Removal of this group ensures destruction of drug activity with the reduction products being transformed into desoxo metabolites. In order to render ring- opening less facile, the oxygen atom at C-10 can be either removed to provide 10-deoxydιhydroartemιsmm, or replaced by other groups, and this has provided the basis for the so-called 'second generation' compounds which are generally 10-deoxy artemisinm derivatives

SUBSTfTUTESHEET(RULE26) In addition, derivatives of artemisinm have also been prepared with a variety of substituents at C-9.

Artemisinm derivatives are also known m which one of the hydrogen atoms m the methyl group attached to the C-9 carbon atom m artemisinm, that is, one of the hydrogen atoms attached to the C-16 carbon- atom, has been replaced by a sulphur-, nitrogen- or carbon- linked group. For instance, Paitayatat et al (J.Med. Chem. ,1997,40,633-638) synthesised, inter alia, two new artemisinm derivatives m which the C-16 carbon atom is substituted by a phenylthio or a ιmιdazol-1-yl group and demonstrated that these compounds are active against Plasmodium falciparum. Avery et al (J.Med. Chem. , 1996 , 39 , 4149-4155) synthesised artemisinm derivatives m which the C-16 carbon atom is substituted by a methyl, ethyl, n-propyl, benzyl or 4-chlorobenzyl group and the five corresponding 10-deoxo derivatives. Moreover, the activity of the five 10-deoxo derivatives against Plasmodium falciparum was also demonstrated. US Patent No. 5216175 also specifically discloses artemisinm derivatives m which the C-16 carbon atom of artemisinm is substituted by a methyl, isopropyl, n-butyl, n-dodecyl or benzyl group and demonstrates activity for these compounds against Plasmodium falciparum.

Whilst the current artemisinm derivatives are successful, there are problems associated with stability, bioavailability and potential neurotoxicity . There is also a need for artemisinm derivatives which exhibit a broad spectrum of activity against a variety of parasites.

It has now been discovered that certain C-9 (C-16) substituted derivatives of artemisinm are effective m the treatment of diseases caused by infection with a parasite These compounds are particularly effective m the treatment of malaria, neospo osis ar coccidiosis, especially forms of these diseases caused by infection with a parasite of the genera Plasmodium, Neospora or Eimeria, particularly Plasmodium falciparum, Neospora caninum and Eimeria tenella. According to the present invention there is therefore provided a compound of the general formula I

or a salt thereof in which W represents a hydrogen atom or an oxo group; and X represents a group -S(0)_nR where n is 0, 1 or 2 , -NR^XR², -CHR³R⁴ or Ar; where

R represents an optionally substituted alkyl, aryl , heterocyclic or polycyclic group; R¹ and R² independently represent an optionally substituted alkyl, cycloalkyl, aryl or aralkyl group; or

R¹ and R² together with the interjacent nitrogen atom represent an optionally substituted heterocyclic group or an amino group derived from an optionally substituted amino acid ester;

R³ represents a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl, aryl or alkoxycarbonyl group; R⁴ represents a nitro group or an optionally substituted alkyl, alkenyl, alkynyl, aryl, alkanoyl , aroyl , alkoxycarbonyl or aryloxycarbonyl group; or R³ and R⁴ together with the interjacent carbon atom represent an optionally substituted cycloalkyl or polycyclic group; and

Ar represents an optionally substituted aryl or heteroaryl group; for use in the treatment and/or prophylaxis of a disease caused by infection with a parasite other than an organism of the genus Plasmodium.

Suitable salts include acid addition salts and these may be formed by reaction of a suitable compound of formula I with a suitable acid, such as an organic acid or a mineral acid. Acid addition salts formed by reaction with a mineral acid are particularly preferred, especially salts formed by reaction with hydrochloric or hydrobromic acid. Compounds of formula I in which X represents a group -NR^-R² where R¹ and R² are as defined above are particularly suitable for the formation of such acid addition salts. Any alkyl, alkenyl or alkynyl group, unless otherwise specified, may be linear or branched and may contain up to 12, preferably up to 6, and especially up to 4 carbon atoms . Preferred alkyl groups are methyl, ethyl, propyl and butyl. When an alkyl moiety forms part of another group, for example the alkyl moiety of an aralkyl group, it is preferred that it contains up to 6, especially up to 4, carbon atoms. Preferred alkyl moieties are methyl and ethyl.

An aryl group may be any aromatic monocylic or polycyclic hydrocarbon group and may contain from 6 to 24, preferably 6 to 18, more preferably 6 to 16, and especially 6 to 14, carbon atoms. Preferred aryl groups include phenyl , naphthyl , anthryl , phenanthryl and pyryl groups, especially a phenyl or naphthyl, and particularly a phenyl, group. When an aryl moiety forms part of another group, for example the aryl moiety of an aralkyl group, it is preferred that it is a phenyl , naphthyl , anthryl , phenanthryl or pyryl , especially a phenyl or naphthyl, and particularly a phenyl, moiety. An aralkyl group may be any alkyl group substituted by an aryl group. A preferred aralkyl group contains from 7 to 16, especially 7 to 10, carbon atoms, a particularly preferred aralkyl group being a benzyl group.

A cycloalkyl group may be any saturated cyclic hydrocarbon group and may contain from 3 to 12 , preferably 3 to 8 , and especially 3 to 6 , carbon . atoms. Preferred cycloalkyl groups are cyclopropyl, cyclopentyl and cyclohexyl groups .

A polycyclic group may be any saturated or partially unsaturated hydrocarbon group which contains more than one ring system. Such ring systems may be "fused", that is, adjacent rings have two adjacent carbon atoms in common, "bridged", that is, the rings are defined by at least two common carbon atoms (bridgeheads) and at least three acyclic chains (bridges) connecting the common carbon atoms, or

"spiro" compounds, that is, adjacent rings are linked by a single common carbon atom. It is also envisaged that a polycyclic group may contain more than one of these types of ring system. Polycyclic groups preferably contain from 4 to 30, particularly 4 to 26, and especially 6 to 18, carbon atoms. Bicyclic, tricyclic and tetracyclic groups are particularly preferred. Preferred bicyclic groups contain from 4 to 14, especially 6 to 10, carbon atoms with bornyl and, particularly, isobornyl groups being especially preferred. Preferred tricyclic groups contain from 5 to 20, especially 6 to 14, carbon atoms with adamantyl groups being especially preferred. Preferred tetracyclic groups contain from 6 to 26, especially 6 to 18, carbon atoms. Cholestanyl and cholestenyl groups are further preferred polycyclic groups.

A heterocyclic group may be any monocyclic or polycyclic ring system which contains at least one heteroatom and may be unsaturated or partially or fully saturated. The term "heterocyclic" thus includes aromatic heterocyclic groups termed "heteroaryl" groups as well as non-aromatic heterocyclic groups. A heteroaryl group may be any aromatic monocyclic or polycyclic ring system which contains at least one heteroatom. Preferably, a heteroaryl group is a 5- to 18- membered, particularly a 5- to 14- membered, and especially a 5- to 10- membered, aromatic ring system containing at 1-east one heteroatom selected from oxygen, sulphur and nitrogen atoms. Preferred heteroaryl groups include pyridyl, pyrylium, thiopyrylium, pyrrolyl , furyl , thienyl , indolinyl, isoindolinyl , indolizinyl, imidazolyl, pyridonyl, pyronyl , pyrimidinyl , pyrazinyl, oxazolyl, thiazolyl, purinyl , quinolinyl, isoquinolinyl , quinoxalinyl , pyridazinyl, benzofuranyl , benzoxazolyl and acridinyl groups. Preferably, a heterocyclic group is a 3- to 18- membered, particularly a 3- to 14- membered, and especially a 5- to 10-membered, ring system containing at least one heteroatom selected from oxygen, sulphur and nitrogen atoms. Preferred heterocyclic groups include the specific heteroaryl groups named above as well as pyranyl , piperidinyl, pyrrolidinyl , dioxanyl , piperazinyl, morpholinyl, tetrahydroisoquinolinyl and tetrahydrofuranyl groups.

An amino acid may be any α-amino acid, such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, cystine, methionine, aspartic acid, glutamic acid, aspargine, glutamine, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, hydroxyproline or phenylglycine, and includes both D- and L- configurations. An amino acid ester may be any ester of such an amino acid, alkyl esters, particularly C_x_₄ alkyl esters, being especially preferred.

When any of the foregoing substituents are designated as being optionally substituted, the substituent groups which are optionally present may be any one or more of those customarily employed in the development of pharmaceutical compounds and/or the modification of such compounds to influence their structure/activity, stability, bioavailability or other property. Specific examples of such substituents include, for example, halogen atoms, nitro, cyano, hydroxyl, cycloalkyl, alkyl, haloalkyl, cycloalkyloxy, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl , alkoxycarbonyl, carboxyl , alkanoyl, alkylthio, alkylsulphinyl , alkylsulphonyl , alkylsulphonato, arylsulphinyl , arylsulphonyl , arylsulphonato, carbamoyl , alkylamido and heterocyclic groups. When any of the foregoing substituents represents or contains an alkyl substituent group, this may be linear or branched and may contain up to 12, preferably up to 6, and especially up to 4, carbon atoms. A cycloalkyl group may contain from 3 to 8 , preferably from 3 to 6, carbon atoms . An aryl group or moiety may contain from 6 to 10 carbon atoms, phenyl groups being especially preferred. A halogen atom may be a fluorine, chlorine, bromine or iodine atom and any group which contains a halo moiety, such as a haloalkyl group, may thus contain any one or more of these halogen atoms .

In one preferred group of compounds W represents a hydrogen atom whereas in another preferred group of compounds W represents an oxo group.

It is preferred that X represents a group -S(0)_nR and R represents a

alkyl, C₆_₁₈ aryl, 3- to 14- membered heterocyclic or C₄_₁₄ bicyclic group, each group being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxyl, C^ alkyl, C₁__i haloalkyl, C_x_₄ alkoxy,

alkoxycarbonyl groups. Preferably, X represents represents a group -S(0)_nR and R represents a Cj . alkyl, C₆.₁₀ aryl, 5- to 10- membered heterocyclic or C_{6 1C} bicyclic group, each group being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxyl, C_1-4 alkyl, C_x_₄ haloalkyl and C_x_₄ alkoxycarbonyl groups.

In a particularly preferred sub-group of compounds, X represents an ethoxycarbonylethylthio, fluorophenylthio, chlorophenylthio, bromophenylthio, naphthylthio, pyrimidinylthio, benzoxazolylthio or hydroxyisobornylthio group. Compounds in which X represents an ethoxycarbonylethylthio, fluorophenylthio or naphthylthio group are particularly preferred. It is also preferred that, when X represents a group -S(0)_nR, n is 0.

In another preferred aspect X may represent a group -NR¹R² where R¹ and R² independently represent a C_LS alkyl, C₆_₁₀ aryl or C₇_₁₆ aralkyl group, or R¹ and R² together with the interjacent nitrogen atom represent a 3- to 14 -membered heterocyclic group, each group being optionally substituted by one or more substituents selected from the group consisting of halogen atoms,

alkoxycarbonyl groups. Preferably, X represents a group - R^² where R¹ and R² independently represent a C_x.4 alkyl or C_7-10 aralkyl group, or R¹ and R² together with the interjacent nitrogen atom represent a 5- to 10- membered heterocyclic group, each group being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, C_x_₄ alkyl, C_1-4 haloalkyl and C^₄ alkoxycarbonyl groups . In a particularly preferred sub-group of compounds, X represents a diethylamino, dibenzylamino, morpholinyl or indolinyl group. Compounds in which X represents a dibenzylamino or indolinyl group are especially preferred. In a further preferred aspect, X may represent a group -CHR³R⁴ where R³ represents a hydrogen atom or a C ,_: alkyl or C, „ alkoxycarbonyl group and R'" represents a nitro, C^ alkyl, C^ alkanoyl, C₇__X1 aroyl , C_x_₆ alkoxycarbonyl or C₆_₁₀ aryloxycarbonyl group, or R³ and R⁴ together with the interjacent carbon atom represent a C_3^8 cycloalkyl or C₄_₂₆ polycyclic group, each group being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxyl, C_x_₄ alkyl, C₁__i haloalkyl, C_1-4 alkoxy and C^ haloalkoxy groups. In particular, X may represent a group represents a group -CHR³R⁴ where R³ represents a hydrogen atom or a C_1-4 alkyl or C^ alkoxycarbonyl group and R⁴ represents a nitro, C_1-4 alkyl, C₁_₄ alkanoyl, benzoyl , C_x_₄ alkoxycarbonyl or benzoxycarbonyl group, or R³ and R⁴ together with the interjacent carbon atom represent a C₃_₆ cycloalkyl, C₆_₁₀ bicyclic or C₆_₁₄ tricyclic group, each group being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxyl, C_x.₄ alkyl and C₁.₄ haloalkyl groups.

In a particularly preferred sub-group of these compounds, X represents a nitromethyl, isopropyl, methoxycarbonylethyl , ethoxycarbonylmethyl , di (ethoxycarbonyl ) methyl , benzoylmethyl, cyclohexyl or adamantyl group. Compounds in which X represents a nitromethyl, isopropyl, methoxycarbonylethyl, ethoxycarbonylmethyl, di (ethoxycarbonyl) methyl or benzoylmethyl group are especially preferred.

In another preferred aspect, X represents a C₆_₁₈ aryl or 5- to 18- membered heteroaryl group, each group being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, C_1-4 alkyl, C^ haloalkyl, C^ alkoxy, di (C^alkyl) amino, C₇_₁₀ aralkyl and heterocyclic groups. Preferably, X represents a C₆_₁₀ aryl group optionally substituted by one or more substituents selected from the group consisting of halogen atoms, C, ₄ alkyl, C, „ alkoxy, di {C_{1 4} alkyl) amino and heterocyclic groups. In a particularly preferred sub-group of compounds, X represents a phenyl, chlorophenyl or bromophenyl group .

Preferably, the parasite is an organism of the genus Neospora or the genus Eimeria .

The present invention also provides the us"e of a compound of the general formula I as defined above for the manufacture of a medicament for the treatment and/or prophylaxis of a disease caused by infection with a parasite other than an organism of the genus Plasmodium. Preferably, the parasite is an organism of the genus Neospora or the genus Eimeria .

According to the present invention there is also provided a compound of the general formula I as defined above, with the provisos that

(l) when X represents a phenylthio, ιmιdazol-1-yl , n-pentyl, n-tridecyl or 2 -methylpropyl group, then W represents a hydrogen atom;

(n) when X represents an n-propyl, n-butyl or (4 -chlorophenyl) ethyl group, then W represents an oxo group ; and

(m) when X represents a group -CHR³R⁴ where R³ represents a hydrogen atom, then R⁴ does not represent a methyl or benzyl group ; for use in the treatment and/or prophylaxis of a disease caused by an infection with a parasite of the genus Plasmodium.

The present invention also provides the use of a compound of the general formula I as defined m the preceding paragraph for the manufacture of a medicament for the treatment and/or prophylaxis of a disease caused by infection with a parasite of the genus Plasmodium

Certain compounds of the general formula I are novel and the invention therefore further provides a compound of the general formula I as defined m the ante-pieceding paragrap^h, witr tne further proviso that, when X represents a group -CHR³R⁴ where R³ represents a hydrogen atom, then R⁴ does not represent an ethyl, n-propyl or 4-chlorobenzyl group.

It should also be appreciated that the compounds of general formula I are capable of existing as different geometric and optical isomers. The 'present invention thus includes both the individual isomers and mixtures of such isomers.

The present invention also provides a novel process for the preparation of a compound of the general formula I as first defined above which comprises reacting artemisitene of the formula II

with a compound of the general formula QNu where Q is a hydrogen or alkali metal atom or a group -MHal, where M is an alkaline earth metal atom and Hal is a halogen atom, and Nu is a nucleophilic group of formula -SR, -NR^XR², -CHR^3'R^4' or Ar where R, R¹, R² and Ar are as defined above, R^3' represents a hydrogen atom or an optionally substituted alkoxycarbonyl group and R⁴' represents a nitro group or an optionally substituted alkanoyl, aroyl , alkoxycarbonyl or aryloxycarbonyl group, to form a compound of formula I in which W represents an oxo group and X represents a group -SR, -NR^², -CHR^3'R^4' or Ar where R, R¹, R², R^3' , R^4' and Ar are as defined above; if desired, reacting a compound of formula I thus formed in which W represents an oxo group and X represents a group -SR with an oxidising agent to form a compound of formula I in which W represents an oxo group and X represents a group -SO-R or -S0₂R; and, if desired, reacting a compound of formula I thus formed with a suitable reducing agent to form a compound of formula I in which W represents a hydrogen atom and X is as defined above. The alkali metal atom may be a lithium, sodium or potassium atom. However, it is particularly preferred that the alkali metal atom is a sodium or lithium, especially a lithium, atom. The alkaline earth metal atom M is preferably magnesium and the halogen atom Hal is preferably a chlorine, bromine or iodine atom.

Compounds of the general formula I which W represents an oxo group and X represents a group -SR, where R is as first defined above, may be conveniently prepared by reacting artemisitene with a thiol of the formula QNu where Q is a hydrogen atom and Nu is a nucleophilic group of formula -SR as defined above. This reaction may be conveniently carried out m the presence of a suitable solvent. Suitable solvents include ethers, especially cyclic ethers, such as tetrahydrofuran. The reaction may also be carried out m the presence of tetrabutylammonium fluoride which facilitates the reaction by providing a fluoride ion which, m turn, acts as a base to deprotonate the thiol . The deprotonation converts the thiol into a thiolate, which is the nucleophile which adds to the exocylic double bond of artemisitene. The HF then protonates the enolate produced m the conjugate addition. Preferably, the reaction is carried out at room temperature, that is, 15 to 35°C, preferably 20 to 30°C.

Suitable oxidising agents for converting compounds of formula I m which W represents an oxo group and X represents a group -SR, where R is as defined above, into compounds of formula I m which W represents an oxo group and X represents a group -SOR or -S0₂R, where R is as defined above, include meta- chloroperbenzoic acid, sodium periodate, dimethyldioxirane , various peracids, acidified hydrogen peroxide and potassium peroxy onosulphate The conversion of a group -SR into a group -SOR may be accomplished by the use of 1.0-1.1 equivalents of meta-chloroperbenzoic acid m a solvent such as diethyl ether or dichloromethane at a temperature below 0°C or by the use of sodium periodate methanol at room temperature. The conversion 'of a group -SR into a group -S0₂R may be accomplished by the use of slightly excess of 2 equivalents of meta-chloroperbenzoic acid in diethyl ether, dichloromethane or a similar solvent at room temperature, an excess of dimethyldioxirane in solvents such as diethyl ether, dichloromethane or similar, or other peracids, acidified hydrogen peroxide or potassium peroxymonosulphate m methanol or aqueous methanol .

Compounds of the general formula I m which W represents an oxo group and X represents a group -NR^XR², where R¹ and R² are as first defined above, may be conveniently prepared by reacting artemisitene with a metallated secondary amine of formula QNu where Q is a lithium atom or a group -MHal , where M is an alkaline earth metal atom, such as magnesium, and Hal is a halogen atom and Nu is a nucleophilic group of formula -NR¹R² as defined above. This reaction may be conveniently carried out in the presence of a suitable solvent. Suitable solvents include ethers, especially cyclic ethers, such a tetrahydrofuran. Preferably, the reaction is carried out at a temperature of -80 to -60°C, particularly -80 to -70°C, and especially -78°C.

The metallated secondary amme may be conveniently prepared by reacting a secondary amme of formula HNR^XR² , where R¹ and R² are as first defined above, with a suitable lithiatmg agent or Grignard reagent Suitable lithiatmg agents include n- , sec- or tert- butyllithium or a similar alkyllithium reagent Suitable Grignard reagents include methyl or ethyl magnesium bromide or iodide. Preferably, the reaction is carried out in the presence of a suitable solvent, particularly an ether solvent such as tetrahydrofuran or diethyl ether, at a temperature of 0°C or below, usually about -78°C.

Compounds of the general formula I in which W represents an oxo group and X represents a group -CHR³'R^4', where R^3' and R^4' are as defined above, may be conveniently prepared by reacting artemisitene with a lithiated acetyl reagent of formula QNu where Q is a lithium atom and Nu is a nucleophilic group of formula -CHR³'R^4' as defined above. This reaction may be conveniently carried out in the presence of a suitable solvent. Suitable solvents include ethers, especially cyclic ethers, such as tetrahydrofuran. Preferably, the reaction is carried out at a temperature of -80 to -60°C, particularly -80 to -70°C, and especially -78°C.

The lithiated acetyl reagent may be conveniently prepared by reacting an acetyl compound of formula

CH₂R^3'R^4', where R^3' and R^4' are as defined above, with a suitable lithiating agent. Suitable lithiating agents for this reaction include lithium diisopropylamide or a similar lithium dialkylamide base or lithium hexamethyldisilazide . Preferably, the reaction is carried out in the presence of a suitable solvent, particularly an ether solvent such as tetrahydrofuran or diethyl ether, at a temperature of 0°C or below, usually about -78°C Alternatively, compounds of the general formula I in which W represents an oxo group and X represents a group -CHR^3'R^4', where R^3' and R^4' are as defined above, may be conveniently prepared by reacting artemisitene with a reagent of formula QNu where Q is a sodium atom and Nu is a nucleophilic group of formula -CHR^'R^4' as defined above. This reaction may be conveniently carried out under an inert atmosphere, such as nitrogen, in the presence of a suitable solvent. Suitable solvents include ethers, especially cyclic ethers, such as tetrahydrofuran. Preferably, the reaction is carried out at a temperature of -5 to + 5°C, especially about 0°C.

The reagent of formula QNu where Q is a sodium atom and Nu is a nucleophilic group of formula -CHR³'R^4' as defined above may be conveniently prepared by reacting, for instance, sodium hydride with a compound of formula CH₂R^3'R⁴' , where R^3' and R^4' are as defined above.

Compounds of the general formula I in which W represents an oxo group and X represents a group -CHR^3'R⁴', where R^3' and R^4' are as defined above, may also be conveniently prepared by reacting artemisitene with a reagent of formula QNu where Q is a hydrogen atom and Nu is a nucleophilic group of formula -CHR^3'R^4' as defined above. This reaction may be conveniently carried out in the presence of a suitable solvent. Suitable solvents include ethers, especially cyclic ethers, such as tetrahydrofuran. Preferably, the reaction is carried out in the presence of tris (dimethylamino) sulphur (trimethylsilyl) difluoride (TASF) and it is preferred that this stage of the reaction is carried out at a temperature of 0°C or below, usually about -78°C. It may also be advantageous, or in some cases necessary, subsequently to add glacial acetic acid to the reaction mixture. This stage of the reaction, if included, may be carried out at room temperature, that is, 15 to 35°C, preferably 20 to 30°C.

In some cases, it may be advantageous or necessary to use a silylated form of the reagent of formula QNu as defined above either to protect a functional group of the reagent during reaction or to stabilise the intermediate carbanion formed during the reaction. Suitable silylated forms of the reagent of formula QNu where Q is as defined above and Nu is a nucleophilic group of formula -CHR^3'R^4' as defined above include compounds in which R^3' and R^4' or a portion thereof has been replaced by a trimethylsilyl group. Such compounds can be prepared by reacting a suitable compound of formula QNu as defined above with ^'a halotrimethylsilane, such as chlorotrimethylsilane or bromotrimethylsilane .

Compounds of the general formula I in which W represents an oxo group and X represents a group Ar, where Ar is as defined above, may be conveniently prepared by reacting artemisitene with a reagent of formula QNu where Q is an alkali metal atom, preferably lithium, or a group -MHal where M is an alkaline earth metal atom, preferably magnesium, and Hal is a halogen atom. This reaction may be conveniently carried out in the presence of a catalytic amount of a copper (I) salt, such as copper (I) iodide, in a suitable solvent. Suitable solvents include ethers, such as diethyl ether and, especially, cyclic ethers, such as tetrahydrofuran. Preferably, the reaction is carried out at a temperature at or below 0°C, preferably about -10°C. In this reaction, the metallated Ar group adds to the exocyclic double bond of artemisitene to form an enolate, which is converted into the desired product of formula I when the reaction mixture is treated with a proton source, such as aqueous ammonium chloride.

The aryl Grignard or aryllithium reagent of formula QNu as defined above may be conveniently prepared by treating a compound of general formula ArHal , where Ar and Hal are as defined above, with either magnesium or lithium metal. Preferably, the reaction is carried out in the presence of a suitable solvent, preferably an ether solvent, such as diethyl ether, tetrahydrofuran or dimethoxyethane .

Suitable reducing agents for forming compounds of the general formula I in which W represents a hydrogen atom and X represents a group -SR, -NR^ , CHR^3'R^4' or Ar, where R, R¹, R², R^3', R^4' and Ar are as defined above, include sodium borohydride in the presence of boron trifluoride dietherate, diisobutylaluminium hydride, similar Lewis acidic metal hydrides dnd triethylsilane . The reduction reaction may be conveniently carried out in the presence of a suitable solvent. Suitable solvents include ethers, especially cyclic ethers, such as tetrahydrofuran. Preferably, the reaction is carried out at a temperature of -5°C to the reflux temperature of the reaction mixture, especially 0°C to reflux temperature. Ideally, the reagents are initially mixed together at 0°C and the reaction mixture is then subsequently heated at reflux temperature .

Depending on the reducing agent and reaction conditions selected, the carbonyl group in the R⁴' moiety of compounds of the general formula I in which W represents an oxo group and X represents a group

-CHR^3'R^4', where R^3' and R^4' are as defined above, may also be reduced to give compounds of the general formula I in which W represents a hydrogen atom and X represents a group -CHR^3'R^4" where R^3' is as defined above and R⁴" is a group -CH₂R^A where R^A is an alkyl, aryl, alkoxy or aryloxy group.

Artemisitene may be prepared by reacting 10-hydro- peroxy-10-dihydroartemisitene (9-hydroperoxy- artemisitene) of formula

with acetic anhydride m the presence of a base, preferably pyrid e. Preferably, the reaction is carried out at room temperature, that is, 15 to 35°C, preferably 20 to 30°C.

10-Hydroperoxy-lO-dιhydroartemιsιtene (9-hydro- peroxyartemisitene) may be prepared by reacting 9,10- anhydrodehydroartemis m of formula

with oxygen m the presence of a solvent, preferably a halogenated hydrocarbon, such as dichloromethane. A photosensitiser, such as methylene blue, is preferably included the reaction mixture to convert ground state (triplet) oxygen into excited state (singlet) oxygen under irradiation from a light source. The active agent which converts the 9 , 10-anhydrodehydro- artemism into 9-hydroperoxyartemιsιtene is therefore singlet oxygen. 9, 10-Anhydrodehydroartemιsmm may be prepared by reacting dihydroartemismm with a dehydrating agent, such as boron tπfluoride dietherate, preferably m the presence of a solvent, especially an ether solvent, such as diethyl ether. Ideally, the reaction is carried out at room temperature, that is, 15 to 35°C, preferably 20 to 30°C.

9 , 10-Anhydroartemιsmm may also be conveniently prepared by reacting dihydroartemismm with tπfluoroacetic anhydride. The reaction may be conveniently carried out in the presence of a solvent, preferably a halogenated hydrocarbon, and especially a chlorinated hydrocarbon, such as dichloromethane. It is also preferred that the reaction is carried out m the presence of a base, such as pyπdme or a derivative thereof, for example, dimethylammo- pyridine Preferably, the reaction is carried out undei an inert atmosphere such as nitrogen, at a temperature of -5°C to +5°C, preferably 0°C, with the reaction mixture being subsequently allowed to warm to room temperature, that is, 15 to 35°C, preferably 20 to 30°C. Dihydroartemisinin, thiols of formula HSR, amines of formula HNR¹R², acetyl compounds of formula - CH₂R^3'R^4' and aryl halide compounds of formula ArHal where R, R¹, R², R^3' , R^4', Ar and Hal are as defined above, are all known compounds or can be prepared by processes analogous to known processes.

Compounds of the general formula I in which X represents a group -CHR³R⁴, where R³ and R⁴ are as first defined above, can also be prepared by reacting artemisitene with a compound of the general formula ZCHR³R⁴, where Z represents a halogen atom and R³ and

R⁴ are as defined above, to form a compound of formula I in which W represents an oxo group and X is as defined above; and, if desired, reacting the compound of formula I thus formed with a suitable reducing agent to form a compound of formula I in which W represents a hydrogen atom and X is as defined above.

Preferred compounds of formula ZCHR³R⁴ are those in which Z represents a chlorine or bromine, especially a bromine, atom. It is also preferred that this reaction is carried out in the presence of a suitable solvent. Suitable solvents include ethers, such as 1, 2-dimethoxyethane. Preferably, the reaction is carried out in the presence of catalytic amounts of an initiator, such as 2 , 2 ' -azobisisobutyronitrile (AIBN, also known as 2 , 2 ' -azobis [2-methylpropane-nitrile] ) , in the presence of tri-n-butyltin hydride. In this context, AIBN converts tri-n-butyltin hydride into the tributyltin radical which abstracts halogen from the compound of formula ZCHR³R⁴ to provide a carbon radical which adds to the exocyclic double bond of artemisitene. After addition, the resulting artemisin radical is reduced by hydrogen atom transfer from the tri-n-butyltin hydride and the chain process is maintained by the tributyltin radical. It is also preferred that the reaction is carried out at a temperature of 60 to 100°C, particularly 70 to 90°C, and preferably 75 to 85°C.

Suitable reducing agents for forming compounds of the general formula I in which W represents a hydrogen atom and X represents a group -CHR³R⁴, where R³ and R⁴ are as defined above, include sodium borohydride in the presence of boron trifluoride dietherate, diisobutylaluminium hydride, similar Lewis acidic metal hydrides and triethylsilane . The reduction reaction may be conveniently carried out in the presence of a suitable solvent, suitable solvents including ethers, such as tetrahydrofuran.

Preferably, the reaction is carried out at a temperature of -5°C to the reflux temperature of the reaction mixture, especially 0°C to reflux temperature. Ideally, the reagents are initially mixed together at 0°C and the reaction mixture is then subsequently heated at reflux temperature.

Artemisitene can be prepared as described above and compounds of formula ZCHR³R⁴ are known compounds or can be prepared by processes analogous to known processes.

The invention also provides a pharmaceutical composition which comprises a carrier and, as active ingredient, a novel compound of the general formula I as defined above. A pharmaceutically acceptable carrier may be any material with which the active ingredient is formulated to facilitate administration. A carrier may be a solid or a liquid, including a material which is normally gaseous but which has been compressed to form a liquid, and any of the carriers normally used m formulating pharmaceutical compositions may be used. Preferably, compositions according to the invention contain 0.5 to 95% by weight of active ingredient .

The compounds of general formula I can be formulated as, for example, tablets, capsules, suppositories or solutions. These formulations can be produced by known methods using conventional solid carriers such as, for example, lactose, starch or talcum or liquid carriers such as, for example, water, fatty oils or liquid paraffins. Other carriers which may be used include materials derived from animal or vegetable proteins, such as the gelatins, dextrins and soy, wheat and psyllium seed proteins; gums such as acacia, guar, agar, and xanthan; polysaccharides ; alginates; carboxymethylcelluloses ; carrageenans ; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; polypeptide/protein or polysaccharide complexes such as gelatin-acacia complexes; sugars such as mannitol, dextrose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminium silicates; and amino acids having from 2 to 12 carbon atoms such as a glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L- phenylalanine.

Auxiliary components such as tablet disintegrants , solubilisers, preservatives, antioxidants , surfactants, viscosity enhancers, colouring agents, flavouring agents, pH modifiers, sweeteners or taste- masking agents may also be incorporated into the composition. Suitable colouring agents include red, black and yellow iron oxides and FD & C dyes such as FD & C blue No. 2 and FD & C red No. 40 available from Ellis & Everard. Suitable flavouring agents include mint, raspberry, liquorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavours and combinations of these. Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Suitable sweeteners include aspartame, acesulfame K and thaumatin. Suitable taste-masking agents include sodium bicarbonate, ion-exchange resins, cyclodextrin inclusion compounds, adsorbates or microencaps^'ulated actives .

For treatment of and prophylaxis against coccidiosis and related parasites, for instance, in poultry, especially in chickens, ducks, geese and turkeys, 0.1 to 100 ppm, preferably 0.5 to 100 ppm of the active compound may be mixed into an appropriate, edible material, such as nutritious food. If desired, the amounts applied can be increased, especially if the active compound is well tolerated by the recipient. Accordingly, the active compound can be applied with the drinking water.

For the treatment of a single animal, for instance, for the treatment of coccidiosis in mammals or toxoplasmosis, amounts of 0.5 to 100 mg/kg body weight active compound are preferably administered daily to obtain the desired results. Nevertheless, it may be necessary from time to time to depart from the amounts mentioned above, depending on the body weight of the experimental animal, the method of application, the animal species and its individual reaction to the drug or the kind of formulation or the time or interval in which the drug is applied. In special cases, it may be sufficient to use less than the minimum amount given above, whilst in other cases the maximum dose may have to be exceeded. For a larger dose, it may be advisable to divide the dose into several smaller single doses.

The invention also provides a method for treating a disease caused by infection with a parasite other than an organism of the genus Plasmodium which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of the general formula I as first defined above. Preferably, the parasite is an organism of the genus Neospora or the genus Eimeria . A method for treating a disease caused by infection with a parasite of the genus Plasmodium is also provided which comprises administering to a host m need of such treatment a therapeutically effective amount of a compound of the general formula I as first defined above with the provisos that d) when X represents a phenylthio, ιmιdazol-1-yl , n-pentyl, n-tπdecyl or 2 -methylpropyl group, then W represents a hydrogen atom; (n) when X represents an n-propyl, n-butyl or (4 -chlorophenyl) ethyl group, then W represents an oxo group ; and

(m) when X represents a group -CHR³R⁴ where R³ represents a hydrogen atom, then R⁴ does not represent a methyl or benzyl group . The invention is further illustrated by the following examples.

Example 1

Preparation of 16- (2 ' -naphthylthio) artemisinm (9- (2- naphthylthiomethyl) artemisinm) (Formula I: W - =0; x = -SR; R = 2 -naphthyl) .

(a) Preparation of 9 , 10-anhydro-lO-deoxoartemιsmm

( 9 , 10 -anhydrodehydroartemismm)

To a solution of dihydroartemismm (10 4 g) in diethyl ether (550 ml ⁾ at room temperature under nitrogen was added dropwise boron trifluoπde dietherate (1.0 ml). The solution was stirred at room temperature overnight, washed with 5% NaHC0₃ solution (3x100 ml) ; dried (MgS0₄) and concentrated m vacuo . The residue was then purified by flash chromatography (Sι0₂; 10% ethyl acetate/hexanes) to give 9 , 1 θ^'-anhydro -10-deoxoartemιsmm (9 , 10-anhydrodehydroartemιsmm) as a white solid (16.8 g, 97%) . δ_H: 6.20 (1H, q, J = 1.41 Hz, H-10) , 5.55 (1H, s, H-12), 2.33-3.50 (1H, m) , 1.03-2.18 (10H, m) , 1.60 (3H, d, J = 1.41 Hz, H16), 1.44 (3H, s, H-14) , 1.00 (3H, d, J = 5.98 Hz, H-15) . (b) Preparation of 10-hydroperoxy- 10 -dihydro- artemis11ene ( 9 -hydroperoxyartemisitene)

To a solution of 9 , 10-anhydro-lO-deoxoartemιsmm (9, 10-anhydrodehydroartemιsmm) (5.32 g, 19.9mmol) prepared as described in (a) above m dichloromethane (250 ml) was added methylene blue (2 mg) . The light blue solution was bubbled with oxygen for 10 minutes after which the solution was then irradiated under an oxygen atmosphere. After completion of reaction, the solution was concentrated m vacuo. The residue was then purified by flash chromatography (Sι0₂; gradient elution; ethyl acetate/hexanes 20:80 to 30:70) to give two white solids. The less polar product was the ring opened formyl aldehyde (0.58g, 9.7%) and the more polar product was the desired hydroperoxide (2.13 g, 36%) . Hydroperoxide: m.p. 149-150°C; [α]_D ²⁰: +162 (c=0 06, CHC1₃) , δ_H: 10.2 (1H, s, OOH) , 5.88 (1H, s, H 12) , 5 76 (1H, s, H-10), 5.33 (1H, s, =CH₂), 5 20 (1H, s, =CH ) , 1 48 (3H, s, H-14), 0 99 (3H, d, J = 5 . 84 Hz , H - 15 ) .

Formyl aldehyde: m.p. 103-104°C; [α]_D ²⁰: -59 (c=0.05 CHC1₃) ; δ_H: 7.94 (1H, s, H-10), 6.58 (1H, s, H-12), 2.52 (3H, s, CH₃CO) , 1.48 (3H, s, H-14), 1.05 (3H, d, J = 6.24 Hz, H-15) . (c) Preparation of artemisitene

To a solution of hydroperoxide (2.00 g, 6.67 mmol) prepared as described m (b) above m acetic anhydride (24 ml) was added pyπdme (1.2 ml) . The mixture was stirred at room temperature for 1 hour. The solution was washed with 1 N hydrochloric acid (3 x 10 ml) , 5% NaHC0₃ solution (3 x 10 ml) and water (3 x 10 ml) ; dried (MgS0₄) and concentrated m vacuo. The residue was then purified by flash chromatography (Sι0₂, ethyl acetate/ hexanes 25:75) to give artemisitene as a white solid (1.72 g, 92%) . m.p. 161-162°C; [ ] _D ²⁰ : +132 (c=0.06 CHCI₃) ; δ_H : 6.58 (1H, s, =CH₂) , 6.01 (1H, s, =CH₂) , 5.69 (1H, s, H-12), 2.50 (1H, dd, J = 13.5, 4.45 Hz), 2.38-2.48 (1H, m) , 1.97-2.11 (2H, m) ,

1.73-1.83 (2H, ) , 1.40-1.69 (4H, m) , 1.47 (3H, s, H-14), 1.15-1.27 (1H, m) , 1.03 (3H, d, J = 5.62 Hz, H-15) . (d) Preparation of 16- (2 ' -naphthylthio) artemisinm (9- ( 2 -naphthylthiomethyl) artemisinm) (Formula I: W = =0 ; X = -SR; R = 2 -naphthyl)

To a solution of artemisitene (280 mg, 1.00 mol) prepared as described m (c) above in tetrahydrofuran (15 ml) was added 2 -naphthalenethiol (160 mg , 1 00 mmol) and tetrabutylammonium fluoride (30 μl , 30 μmol) at room temperature under nitrogen The mixture was stirred at room tempeiature for a further 4 hours The solution was then concentrated in vacuo. The residue was purified by flash chromatography (Si0₂; 25% ethyl acetate/hexanes) to give 16- (2 ' naphthylthio) artemisinin (9- (2 -naphthylthiomethyl) artemisinin) as a white solid (368mg, 84%). M.p. 49.8-52.2°C; [or] _D ²⁰ : +162.38° (c = 1.01, CHC1₃) ; IR (neat) v_max : 3061, 2926, 2870, 1730, 1626, 1590, 1500, 1452, 1376, 1212, 1104, 1032, 1010, 978, 942, 876, 814, 746; δ_H (300 MHz): 7.78-7.84 (4H, m, Ar-H) , 7.46-7.51 (3H, m, Ar-H), 5.94 (1H, s, H-12), 5.90 (1H, s, H-12), 4.03 (1H, dd, J = 13.8, 3.31 Hz, H-16), 3.94 (1H, dd, J = 13.6, 4.44 Hz, H-16), 3.24 (1H, dd, J = 13.8, 11.7 Hz, H-16), 2.95 (1H, dd, J = 13.6, 11.8 Hz, H-16), 2.40-2.50 (1H, m, H-4α) , 3.35 (1H, ddd, J = 11.5, 3.30, 0.75 Hz, H-9), 2.28 (1H, dd, J = 13.0, 4.29 Hz, H-5a) , 2.05-2.13 (1H, m, H-4S) , 1.95-2.00 (1H, m, H-5c.) , 1.14-1.70 (7H, m, H-8α, H-7S, H-8a, H-6, H-5β, H-7α, H-8S) , 1.49 (3H, s, H-14), 1.00 (3H, d, J = 6.07 Hz, H-15). δ_c: 171.21, 134.42, 132.68, 129.45, 128.36, 127.82, 127.33, 126.53, 106.12, 94.73, 81.42, 51.01, 44.02, 41.94, 38.42, 36.51, 34.49, 31.97, 26.13, 25.38, 20.48; MS (CI positive, CH₄) m/z: 469 ((MH+C₂H₈)⁺, 7.4%), 442 (MH⁺, ¹³C, 6.5%), 441 (MH⁺, 28%), 440 (M⁺, 16%), 425 (M-0)⁺, 16%); Anal. Calc. For C₂₅H₂₈0₅S: C, 68.16, H, 6.41; Found: C, 68.23, H, 6.70.

Example 2

Preparation of 10-deoxo-16- (2 ' -napthylthio) -10- dihydroartemisinin (10-deoxo-9- (2 -naphthylthiomethyl) - artemisinin) (Formula I : W= -H; X = -SR; R = 2- naphthyl)

To a suspension of sodium borohydride (61.2 mg, 1.61 mmol) m tetrahydrofuran (5 ml) at 0°C under nitrogen was added a precooled (0°C) solution of 16- (2'- naphthylthio) artemisinin (9- (2 -naphthylthiomethyl ) artemisinm) prepared as described Example 1 above (337mg, 0.765 mmol) and boron tπfluoride dietherate (2.80 ml) m tetrahydrofuran (5 ml) . The mixture was stirred at 0°C for 1 hour and then heated at reflux for 10-30 minutes. TLC indicated complete consumption of the 10-oxo compound. The reaction was poured into ice-water and stirred for 30 minutes, extracted with diethyl ether (3 x 30 ml) , dried (MgS0₄) and concentrated m vacuo . The residue was purified by flash chromatography (Sι0₂; 10% ethyl acetate/hexanes) to give 10-deoxo-16- (2 ' -naphthylthio) -10- dihydroartemismm (10-deoxo-9- (2 -naphthylthiomethyl) artemisinm) as a white solid (65.9 mg, 20%) . δ_H : 7.74-7.81 (4H, m, Ar-H), 7.41-7.51 (3H, m, Ar-H), 5.21 (1H, s, H-12), 4.14-4.18 (1H, m, H-16), 3.88 (1H, dd, J = 12.1, 3.52 Hz, H-16), 3.60 (1H, dd, J = 13.5, 8.65 Hz, H-10), 3.52 (1H, dd, J = 13.5, 6.32 Hz, H-10), 2.38 (1H, ddd, J = 17.3, 13.4, 3.85 Hz), 2.08 (1H, ddd, J = 17.8, 7.71, 4.64 Hz), 1.89-1.94 (2H, m) , 1.11-1.70 (8H, m) , 1.47 (3H, s, H-14), 0.98 (3H, d, J = 5.71 Hz, H-15); m/z (CI, NH₃) : 444 (M+NH₄\ 100%), 427 (M=⁺+l, 48), 367 (24), 160 (2).

Example 3

Preparation of 16- (N,N-dιbenzylammo) artemisinm (9- (N,N-dιbenzylammomethyl) artemisinm) (Formula I:W= =0; X = -NR'R²; R¹ = R² = benzyl) .

To a solution of dibenzylamme (llOμl, 0.550 mmol) m tetrahydofuran at -78°C under nitrogen was added dropwise n-butyllithium (220 μl , 0.550 mmol, 2.5 M) . The solution was stirred for a further 15 minutes. A precooled (0°C) solution of artemisitene (140mg, 0.500 mmol prepared as described m Example 1(c) above m tetrahydrofuran was then added dropwise through cannula to the above solution The mixture was stirred for a further 1 hour, then quenched with saturated NH₄C1 solution, extracted with diethyl ether (3 x 15 ml), dried (MgSO and concentrated m vacuo The residue was purified by flash chromatography (Si0₂; 20% ethyl acetate/hexanes) to give 16-(N,N- dibenzylamino) artemisinin (9- (N, N-dibenzylamino- methyl) artemisinin) as a colourless oil (150mg, 63%) . δ_H 7.23-7.38 (10H, m, Ar-H), 5.86 (1H, s, H-12), 3.77 (2H, d J = 13.6 Hz, (PhCH₂)₂N), 3.50 (2H, d J = 13.6 Hz, (PhCH₂)₂N), 3.04-3.16 (2H, m, H-16), 2.18-2.30 (2H, m) , 1.88-2.07 (3H, m) , 1.65-1.71 (1H, m) , 0.86-1.50 (6H, m) , 1.41 (3H, s, H-14), 1.00 (3H, d, J = 6.15 Hz, H-15); δ_c : 170.75, 139.17, 129.05, 128.13, 126.87, 104.97, 93.68, 80.23, 58.73, 58.51, 50.17, 43.78, 39.81, 37.46, 35.66, 34.06, 31.03, 25.33, 24.63, 19.83; m/z (CI, CH₄) 478 (M⁺+l, 20), 298 (100), 268 (34) , 198 (6) .

Example 4

Preparation of a 16- [di (ethoxycarbonyl) methyl] - artemisinin (9- [2 , 2-di (ethoxycarbonyl) ethyl] - artemisinin) (Formula I : W = =0 ;X=-CHR³R⁴ ; R³ = R⁴ = -C0-0CH,H .

To an ice-cold solution of malonic acid diethyl ester (800.8 mg, 5 mmol) in 10 ml tetrahydrofuran was slowly added sodium hydride (218.2 mg, 5 mmol, 55% in paraffin oil) . The resulting solution was then added to an ice-cold solution of artemisitene (1.4 g, 5 mmol) prepared as described in Example 1 (c) above in 20 ml tetrahydrofuran under nitrogen. The mixture was stirred for 4 hours at 0°C, then at room temperature overnight. After this, it was poured into 50 ml ice- water, neutralised and extracted with ether. After drying over MgS0₄ , the solvent was evaporated and the residue purified by column chromatography to give 16- [di (ethoxycarbonyl) methyl] artemisinin (9- [2 , 2-di- (ethoxycarbonyl) ethyl] artemisinin) (785.1 mg, 35.6%); δ_H: 5.92 (1H, s, H-12), 4.12-4.30 (2x2H, m,

OCH₂CH₃) , 3.90 (1H, dd, J=9.08, 6.44 Hz, H-17) , 2.58- 2.65 (1H, m, H-9) , 1.01-1.31 (2x3H, m, OCH₂CH₃) , 1 . 00 ( 3H , d , J=5 . 80 Hz , H- 15 ) .

Example 5

Preparation of 16- [ (ethoxycarbonyl) methyl] artemisinin (9- [2- (ethoxycarbonyl) ethyl] artemisinin) (Formula I : W = =0; X = -CHR³R⁴; R³ = H ; R⁴ = -CO-OCH Method 1 Artemisitene (280 mg, 1 mmol) prepared as described in Example 1 (c) above was dissolved in dry tetrahydrofuran (5 ml) under nitrogen and the silylated reagent acetic acid ketene-ethyltrimethyl- silylacetal (2 mmol) was added at a temperature of 0°C. Subsequently, this mixture was added to a -78°C cold suspension of tris (dimethylamino) sulphur

(trimethylsilyl) difluoride (TASF) (56 mg, 0.2 mmol) in tetrahydrofuran (5ml) and the reaction was stirred at -78°C overnight. Glacial acetic acid (40 ml) was added and the mixture stirred for a further 30 minutes at room temperature. After this time, the solvent was evaporated and the residue was dried in vacuo before purification by flash chromatography (Si0₂; 28% ethyl acetate/hexanes) to give 16- [ (ethoxycarbonyl) - methyl] artemisinin (9- [2- (ethoxycarbonyl) ethyl] - artemisinin) (109.9 mg, 29.8%) as an oil.

Method 2

A solution of ethyl acetate (105μl, 1.10 mmol) in tetrahydrofuran (5 ml) at -78°C under nitrogen was added dropwise to lithium diisopropylamide (0.74 ml, 1.10 mmol, 1.5 M) . The mixture was stirred at -78 °C for a further 15 minutes after which it was then added dropwise to a solution of artemisitene (280 mg, 1.00 mmol) prepared as described in Example 1 (c) above in tetrahydrofuran (5 ml) at -78°C. The solution was stirred for a further 1 hour, quenched with saturated NH..C1 solution, extracted with diethyl ether '3 15 ml) ; dried (MgS0₄) and concentrated in vacuo. The residue was purified by flash chromatography (Si0₂; 28% ethyl acetate/hexanes) to give 16- [ (ethoxycarbonyl) methyl] artemisinin (9- [2- (ethoxy- carbonyl) ethyl] artemisinin) as a colourless oil

(209mg, 57%). [a] _D ²⁰ +81.5° (c 0.055 CHCl₃) ; δ_H ^' : 5.92 (1H, s, H-12), 4.13 (2H, q, J = 7.16 Hz, 0CH₂CH₃) , 2.22-2.66 (6H, m) , 1.90-2.13 (3H, m) , 1.69-1.86 (3H, m) , 1.05-1.57 (4H, m) , 1.46 (3H, s, H-14), 1.26 (3H, t, J = 7.16 Hz, 0CH₂CH₃) , 1.00 (3H, d, J = 5.90 Hz, H-15); δ_c : 173.08, 171.14, 105.14, 93.69, 79.98, 60.23, 50.35, 43.66, 43.64, 37.41, 35.78, 33.82, 30.85, 31.21, 29.31, 25.32, 24.54, 19.72, 14.08; m/z (CI, CH₄) : 369 (M⁺+l, 30%), 323 (32), 305 (68), 277 (100), 259 (44) . Anal. Calcd. for C₁₉H₂₈0₇: C, 61.94; H, 7.66; found: C, 62.23, H, 7.64.

Example 6

Preparation of 10-deoxo-16- [2- (ethoxycarbonyl) methyl] - 10-dihydroartemisinin (10-desoxo-9- \2 - (ethoxycarbonyl) ethyl] artemisinin) (Formula I : W = -H; X = CHR³R⁴ ,• R³ = H; R⁴ = -CO-OCHJ

16- [ (Ethoxycarbonyl) methyl] artemisinin (9- [2- (ethoxycarbonyl) ethyl] artemisinin) (0.5 mmol) prepared as described in Example 5 above was mixed with boron trifluoride etherate (1.86 ml, 15 mmol) in tetrahydrofuran (5 ml) under nitrogen with ice-cooling. This solution was added to a suspension of sodium borohydride (44 mg, 1.12 mmol) in 5 ml tetrahydrofuran at 0°C. The mixture was stirred under nitrogen at 0°C for a further 3 hours and then boiled for 10 minutes. Subsequently, ice was added to the cooled solution and the latter neutralised with NaHC0₃ and extracted with ether. The solvent was evaporated and the residue purified by column chromatography to give 10-deoxo-16- [ (ethoxycarbonyl ) methyl] artemisinin (10-desoxo- 9- [2 - (ethoxycarbonyl ) ethyl] artemisinin) as an oil (23.6 mg , 13.4 %) ; δ„: 4.94 (1H, s, H-12), 4.12 (2H, q, J=7.14 Hz, OCH₂CH₃) , 3.75-3.87 (2H, m, H-10), 3.40-3.56 (2H, m, H-17) , 1.17-2.46 (14H, m) , 1.55 (3H, s, H-14), 1.25 (3H, t, J=7.14 Hz, OCH₂CH₃) , 1.01 (3H, d, J=6.27 Hz, H- 15) .

Example 7

Preparation of 16- (2 ' -propyl) rtemisinm (9- (2- methylpropyl) artemisinm) (Formula I : W = =0 ; X = - CHR³R⁴; R³ = R⁴ = CH,)

To a solution of artemisitene (280 mg, 1.00 mmol) prepared as described m Example 1 (c) above and 2 -bromopropane (140μl, 1.50 mmol) m 1 , 2-dιmethoxyethane (15 ml) was added a catalytic amount of AIBN (50 mg) . The mixture was heated at 80°C for 3 hours. The solution was concentrated m vacuo . The residue was then purified by flash chromatography (Sι0₂; 15% ethyl acetate/hexanes) to give 16- (2'- propyl) artemisinm ( 9- (2 -methylpropyl) artemisinm) as a white solid (0.293g, 90%). M.p. 105.5-106.6°C; [a] _D ²⁰ : +79.7° (c 0.37/CHCl₃); _max (film) 2956, 2870, 1738, 1456, 1376, 1198, 1154, 1108, 1032, 1006, 982, 938, 876, 832, 760; δ_H 5.92 (1H, s, H-12), 2.36-2.46 (1H, m) , 2.22-2.27 (1H, m) , 1.88-2.16 (3H, m) , 1.62-1.83 (5H, m) , 1.05-1.58 (5H, m) , 1.47 (3H, s, H-14), 1.01 (3H, d, J = 5.80 Hz, H-15), 0.96 (3H, d, J = 6.34 Hz, CH₃CHCH₃) , 0.91 (3H, d, J = 6.34 Hz, CH₃CHCH₃) ; m/z (CI, CH₄) 325 (M⁺+l, 28%), 308 (56), 291 (40), 279 (56), 261 (68), 251 (100), 221 (26); Anal.Calc. for C₁₈H₂₈0₅: C, 66.64; H, 8.70; Found: C, 66.38, H, 8.77.

Example 8

Preparation of 16- (N- 1 ' -indolinyl ) artemisinm (Formula I: X = - R^²; R7R² = l'-mdolyl, W= =0. To a solution of doline (135 μl, 1.2 mmol) m tetrahydofuran at -78°C under nitrogen was added dropwise n-butyll lthi ^ (440 μl, 1 1 mmol, 2 5 M) The solution was stirred for a further 15 minutes. A precooled (0°C) solution of artemisitene (280 mg, 1.00 mmol prepared as described in Example 1(c) above in tetrahydrofuran was then added dropwise through cannula to the above solution. The mixture was stirred for a further 1 hour, then quenched with saturated NH₄C1 solution, extracted with diethyl ether (3 x 15 ml) , dried (MgS0₄) and concentrated in vacuo . The residue was purified by flash chromatography (Si0₂; 23% ethyl acetate/hexanes) to give 16- (N- l ' -indolyl) artemisinin, M.p. 64.9-65.1 °C; [a] _D ²⁰ +74.4° (c 0.018/CHCl₃) ; _maχ (film) : 2926, 1732, 1606, 1488, 1456, 1376, 1276, 1228, 1154, 1126, 1106, 1030, 998, 880, 830, 748; δ_H 7.08- 7.12 (2H, m, Ar-H), 6.59-6.72 (2H, m, Ar-H), 6.00 (1H, s, H-12), 3.81 (1H, dd, J^" = 13.5, 11.3 Hz, ArCH₂) , 3.57 (1H, ddd, J^" = 9.06, 8.89, 5.24 Hz, NCH₂) , 3.49 (1H, dd, J = 13.5, 4.79 Hz, ArCH₂) , 3.29 (1H, ddd, J^" = 9.33, 9.06, 8.89 Hz, NCH₂) , 2.93-3.12 (2H, m, H-16), 2.42-2.62 (2H, m) , 1.94-2.17 (3H, m) , 1.37-1.75 (6H, m) , 1.51 (3H, s, H-14), 1.09-1.22 (1H, m) , 1.00 (3H, d, J = 5.89 Hz), H-15); δ_c 170.21, 152.44, 129.36, 127.37, 124.32, 117.61, 106.73, 105.32, 93.80, 80.39, 54.14, 53.73, 50.22, 44.29, 39.59, 37.45, 35.75, 33.78, 31.28, 28.50, 25.35, 24.65, 19.72; m/z (CI, CH₄) : 400 (M⁺+l, 100), 399 (M⁺, 76), 371 (14), 132

(90); Anal. Calc. for C₂₃H₂₉N0₅ : C, 69.15; H, 7.32; N, 3.50; Found , 69.28; H, 7.33; N, 3.31.

Example 9 Preparation of 16- (4 ' -bromophenyl) artemisinin (Formula I : W = =0 ; X = -Ar; Ar = p-BrCH -)

To a solution of artemisitene (140 mg, 0.500 mmol) in THF (8 mL) containing Cul (10 mg , cat.) at -10 °C under nitrogen was added dropwise a solution of 4- bromophenylmagnesium bromide (600 μl, 0.550 mmol, 1.0 M in diethyl ether, 1.10 eq. The mixture was stirred at -10 °C for a further 15-30 mm. It was then treated with saturated aqueous NH₄C1 solution and the mixture was allowed to warm to room temperature. After separation of the organic layer, the aqueous solution was extracted with Et₂0 (2 x 25 mL) . The combined organic layer was washed with brine, dried (MgS0₄) and concentrated in vacuo to leave the crude mixture of diastereomeric adducts (7.8:1, 150 mg, 76%). This mixture was submitted to flash chromatography (Si0₂; 25% ethyl acetate/hexanes mixture) to give firstly the minor isomer, and then the major isomer of 16- (4'- bromophenyl) artemisinin as white solid, m.p. 53.2-54.2 °C; [α]_D ²⁰ +160° (c 0.022 CHCl₃) ; v_max (film) 2926, 1732, 1488, 1450, 1376, 1214, 1106, 1072, 1032, 1012, 998, 946, 880, 830, 760; δ_H: 7.10-7.45 (4H, m, Ar-H), 5.92 (1H, s, H-12), 3.47 (1H, dd, J= 13.74, 4.33 Hz, H-16), 2.97 (1H, dd, J= 13.74, 11.81 Hz, H-16), 2.36-2.47 (2H, m) , 1.91-2.11 (2H, m) , 1.13-1.69 (7H, m) , 1.48 (3H, s, H-14), 0.84-1.02 (1H, m) , 0.94 (3H, d, J= 5.91 Hz, H-15); δ_c: 171.19, 137.95, 131.67, 130.98, 105.37, 93.87, 80.38, 50.33, 46.33, 40.51, 39.12, 37.43, 35.85,

33.71, 31.29, 25.40, 24.67, 19.71; m/z (CI, NH₃) 456 (M-⁸¹Br+NH₄ ⁺, 100) , 454 (M-⁷⁹Br+NH₄ ⁺ , 96) , 439 (M-⁸¹Br⁺+l, 6) , 437 (M-⁷⁹Br⁺ + l, 2) ; Anal. Calc . for C₂₁H₂₅Br0₅: C, 57.68; H, 5.76; Found: C, 57.81; H, 5.84.

Examples 10 to 28

By processes similar to those described in Examples 1 to 9 above, further compounds according to the invention were prepared as detailed in Table I below. In this table, the compounds are identified by reference to formula I . Physical data for these compounds are provided in Table IA below.

Table 1 A

Example 29

The parasiticidal activity of compounds of the invention was investigated by means of the following test .

Abbreviations used m the example:

C0₂ = carbon dioxide

DMSO = dimethylsulphoxide

RPMI = growth medium for cell cultures

(a) In Vi tro Screening against Plasmodium Falciparum

Two parasite strains - 2 resistant to chloroquine, and D6 sensitive to chloroqume but resistant to mefloquine were used. In Table II below, the best compounds should show no cross resistance between the two strains.

The assay relies on incorporation of radiolabelled hypoxanthine by the parasite and inhibition of incorporation is attributed to activity of known or candidate antimalaπal drugs. For each assay, proven antimalarials such as chloroquine, mefloquine, quinine, artemisinm and pyrimethamme were used as controls. The incubation period was 66 hours, and the starting parasitemia was 0.2% with 1% hematocrit . The medium was an RPMI-1640 culture with no folate or p-ammobenzoic acid. Albumax rather than 10% normal heat inactivated human plasma was used as, with Albumax, less protein binding is observed, and compounds elicit slightly higher activities m this model. If a compound was submitted with no prior knowledge of activity, it was dissolved directly m dimethyl sulphoxide (DMSO) , and diluted 400 fold with complete culture medium The unknown compound was started at a maximum concentration of 50,000 ng ml ^x and sequentially diluted 2-fold for 11 times to give a concentration range of 1048 fold These dilutions -^ c performed automatically by a Biomel 1000 Liquid Handling System in 96-well microtiter plates. The diluted drugs were then transferred to test plates, 200 μl of parasitized erythrocytes were added, and incubated at 37°C in a controlled environment of 5% C0₂, 5% 0₂ and 90% N₂. After 42 hours, 25 μl of

³H-hypoxanthine was added, and the plates incubated for an additional 24 hours. After 66 hours, the plates were frozen at -70°C to lyse the red cells, and then thawed and harvested onto glass fiber filter mats in a 96-well harvester. The filter mats were then counted in a scintillation counter. For each drug, the concentration response profile was determined and 50%, 90% and 10% inhibitory concentrations (IC₅₀, IC₉₀ and IC₁₀) were determined by a non-linear logistic dose response analysis program.

A prescreen format can be used wherein a 3 -dilution assay may be used to determine activity at high medium or low concentrations. The concentrations were selected as 50,000, 500 and 50 ng ml^"1. These were performed in duplicate on a 96-well format plate with 14 test compounds and one known (standard) compound per plate. The system was automated with a Biomek diluter for mixing and diluting the drugs, and adding drugs and parasites to a test plate. In the prescreen format, if the ANALYSIS FIELD (AF) has a "<", then the compound was "very active" and the IC values are most likely to be below the last dilution value (in nanograms/ml) , which is listed next to AF . In most cases, these compounds were run again at lower starting concentration to determine the true IC value. If the AF has a ">", then the IC value is greater than the prescreen dilution value; thus "AF>250" means that the IC value is greater than 250 ng ml ^Ύ and no further screening is carried out. In such cases, values of 0.00 are entered for IC values.

The results are set out in Table II below:- Table II

Claims

C L A I M S

1 . A compound of the general formula I

or a salt thereof, in which

W represents a hydrogen atom or an oxo group; and X represents a group -S(0)_nR where n is 0, 1 or 2 , -NR^², -CHR³R⁴ or Ar; where

R represents an optionally substituted alkyl, aryl, heterocyclic or polycyclic group; R¹ and R² independently represent an optionally substituted alkyl, cycloalkyl, aryl or aralkyl group; or

R¹ and R² together with the interjacent nitrogen atom represent an optionally substituted heterocyclic group or an amino group derived from an optionally substituted amino acid ester; R³ represents a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl, aryl or alkoxycarbonyl group;

R⁴ represents a nitro group or an optionally substituted alkyl, alkenyl, alkynyl, aryl, alkanoyl, aroyl , alkoxycarbonyl or aryloxycarbonyl group; or

R³ and R⁴ together with the interjacent carbon atom represent an optionally substituted cycloalkyl or polycyclic group; and

Ar represents an optionally substituted aryl or heteroaryl group; for use in the treatment and/or prophylaxis of a disease caused by infection with a parasite other than an organism of the genus Plasmodium.

2. A compound according to claim 1 in which represents a hydrogen atom.

3. A compound according to claim 1 in which W represents an oxo group.

4. A compound according to any one of the preceding claims in which X represents a group -S(0)_nR and R represents a

alkyl, C₆.₁₈ aryl, 3- to 14- membered heterocyclic or C₄_₁₄ bicyclic group, each group being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxyl, C₁__i alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy and C_╬╗_₆ alkoxycarbonyl groups.

5. A compound according to any one of the preceding claims in which X represents a group -S(0)_nR and R represents a C-,_₄ alkyl, C₆_₁₀ aryl, 5- to 10- membered heterocyclic or C_6-10 bicyclic group, each group being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxyl, C _₄ alkyl, C_x_₄ haloalkyl and C_1-4 alkoxycarbonyl groups.

6. A compound according to any one of the preceding claims in which X represents an ethoxycarbonylethylthio, fluorophenylthio, chlorophenylthio, bromophenylthio, naphthylthio, pyrimidinylthio, benzoxazolylthio or hydroxyisobornylthio group.

7. A compound according to any one of the preceding claims in which X represents an ethoxycarbonylethylthio, fluorophenylthio or naphthylthio group.

8. A compound according to any one of the preceding claims in which X represents a group -S(0)_nR where n is 0.

9. A compound according to any one of claims 1 to 3 in which X represents a group -NR*R² where R¹ and R² independently represent a C_╬╗_₆ alkyl, C₆_₁₀ aryl or C_7^16 aralkyl group, or R¹ and R² together with the interjacent nitrogen atom represent a 3- to 14- membered heterocyclic group, each group being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, C_1-4 alkyl, C_x.₄ haloalkyl and Cj_.₆ alkoxycarbonyl groups.

10. A compound according to claim 9 in which X represents a group -NR^LR² where R¹ and R² independently represent a C_1-4 alkyl or C₇_₁₀ aralkyl group, or R¹ and R² together with the interjacent nitrogen atom represent a 5- to 10- membered heterocyclic group, each group being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, C₁.₄ alkyl, C_1-4 haloalkyl and C-,_₄ alkoxycarbonyl groups .

11. A compound according to claim 9 or claim 10 in which X represents a dibenzylamino or indolinyl group.

12. A compound according to any one of claims 1 to 3 in which X represents a group -CHR³R⁴ where R³ represents a hydrogen atom or a C₁_₆ alkyl or

alkoxycarbonyl group and R⁴ represents a nitro, C_{x 6} alkyl, C^g alkanoyl, C₇__u aroyl , C_{x 6} alkoxycarbonyl or C_6.10 aryloxycarbonyl group, or R³ and R⁴ together with the interjacent carbon atom represent a C_{3 8} cycloalkyl or C ₂₆ polycyclic group, each group being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxyl, C alkyl, C_l__i haloalkyl, C_x_₄ alkoxy and C_1-4 haloalkoxy groups .

13. A compound according to claim 12 in which X represents a group -CHR³R⁴ where R³ represents a hydrogen atom or a C^ alkyl or C_x_₄ alkoxycarbonyl group and R⁴ represents a nitro, C^ alkyl, C₁__i alkanoyl , benzoyl , C^ alkoxycarbonyl or benzoxycarbonyl group, or R³ and R⁴ together with the interjacent carbon atom represent a C₃_₆ cycloalkyl,

C₆_₁₀ bicyclic or C₆_₁₄ tricyclic group, each group being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxyl, C_1-4 alkyl and C_x_₄ haloalkyl groups.

14. A compound according to claim 12 or claim 13 in which X represents a nitromethyl, isopropyl, methoxycarbonylethyl , ethoxycarbonylmethyl , di (ethoxycarbonyl) methyl , benzoylmethyl, cyclohexyl or adamantyl group.

15. A compound according to any one of claims 12 to 14 in which X represents a nitromethyl, isopropyl, methoxycarbonylethyl , ethoxycarbonylmethyl , di (ethoxycarbonyl) methyl or benzoylmethyl group.

16. A compound according to any one of claims 1 to 3 in which X represents a C₆ΓÇ₧₁₈ aryl or 5- to 18- membered heteroaryl group, each group being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, C_x_₄ alkyl, C^ haloalkyl, C_x_₄ alkoxy, di (C_1-4 alkyl) amino, C₇_₁₀ aralkyl and heterocyclic groups.

17. A compound according to claim 16 in which X represents a C₆.₁₀ aryl group optionally substituted by one or more substituents selected from the group consistmg of halogen atoms, _{╬╗ 4} alkyl, C_{╬╗ 4} alkoxy. di (C_{x 4}alkyl) ammo and heterocyclic groups.

18. A compound according to claim 16 or claim 17 m which X represents a phenyl, chlorophenyl or bromophenyl group .

19. A compound according to any one of the preceding claims in which the parasite is an organism of the genus Neospora or the genus Eimeria .

20. Use of a compound of the general formula I as defined any one of claims 1 to 18 for the manufacture of a medicament for the treatment and/or prophylaxis of a disease caused by infection with a parasite other than an organism of the genus Plasmodium.

21. Use according to claim 20 which the parasite is an organism of the genus Neospora or the genus

Eimeria .

22. A compound of the general formula I as defined any one of claims 1 to 18, with the provisos that d) when X represents a phenylthio, ιmιdazol-1-yl , n-pentyl, n-tπdecyl or 2 -methylpropyl group, then represents a hydrogen atom;

(n) when X represents an n-propyl, n-butyl or (4 -chlorophenyl) ethyl group, then represents an oxo group ; and

(m) when X represents a group -CHR³R⁴ where R³ represents a hydrogen atom, then R⁴ does not represent a methyl or benzyl group; for use in the treatment and/or prophylaxis of a disease caused by an infection with a parasite of the genus Plasmodium

23. Use of a compound of the general formula I as defined in claim 22 for the manufacture of a medicament for the treatment and/or prophylaxis of a disease caused by infection with a parasite of the genus Plasmodium.

24. A compound of the general formula I as defined in claim 22, with the further proviso that, when X represents a group -CHR³R⁴ where R³ represents a hydrogen atom, then R⁴ does not represent an ethyl, n-propyl or 4-chlorobenzyl group.

25. A process for the preparation of a compound of the general formula I as defined in claim 1 which comprises reacting artemisitene with a compound of the general formula QNu, where Q is a hydrogen or alkali metal atom or a group -MHal, where M is an alkaline earth metal atom and Hal is a halogen atom, and Nu is a nucleophilic group of formula -SR, -NR^², -CHR³'R^4' or Ar where R, R¹ , R² and Ar are as defined in claim 1, R³' represents a hydrogen atom or an optionally substituted alkoxycarbonyl group and R^4' represents a nitro group or an optionally substituted alkanoyl, aroyl, alkoxycarbonyl or aryloxycarbonyl group, to form a compound of formula I in which W represents an oxo group and X represents a group -SR, -NR^-R², -CHR^3'R^4' or Ar where R, R¹, R², R^3' , R^4' and Ar are as defined above; if desired, reacting a compound of formula I thus formed in which represents an oxo group and X represents a group -SR with an oxidising agent to form a compound of formula I in which W represents an oxo group and X represents a group -SO-R or -S0₂R; and, if desired, reacting a compound of formula I thus formed with a suitable reducing agent to form a compound of formula I in which represents a hydrogen atom and X is as defined in claim 1.

26. A process for the preparation of a compound of the general formula I as defined in claim 1 in which X represents a group -CHR³R⁴, where R³ and R⁴ are as defined in claim 1, which comprises reacting artemisitene with a compound of the general formula ZCHR³R⁴, where Z represents a halogen atom and -R³ and R⁴ are as defined above, to form a compound of formula I in which represents an oxo group and X is as defined above; and, if desired, reacting the compound of formula I thus formed with a suitable reducing agent to form a compound of formula I in which represents a hydrogen atom and X is as defined above.

27. A pharmaceutical composition which comprises a carrier and, as active ingredient, a compound of the general formula I according to claim 24.

28. A method for treating a disease caused by infection with a parasite other than an organism of the genus Plasmodium which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of the general formula I as defined in claim 1.

29. A method for treating a disease caused by infection with a parasite of the genus Plasmodium which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of the general formula I as defined in claim 22.