MXPA01000396A - Antiparasitic artemisinin derivatives (endoperoxides) - Google Patents

Abstract

This invention relates to the use of certain C-10 substituted derivatives of artemisinin of general formula (I) in the treatment and/or prophylaxis of diseases caused by infection with a parasite, certain novel C-10 substitued derivatives of artemisinin, processes for their preparation and pharmaceutical compositions containing such C-10 substituted derivatives. The compounds are particularly effective in the treatment of malaria, neosporosis and coccidiosis.

Description

DERIVATIVES OF ARTEMISININ ANTIPARASITICOS (ENDOPEROXIDOS) This invention describes the use of certain substituted C-10 derivatives of artemisinin in the treatment and / or prophylaxis of diseases caused by infection with a parasite, certain new C-10 substituted derivatives of artemisinin, the processes for its preparation and the pharmaceutical compositions containing such C-10 substituted derivatives. Malaria is the most important human parasitic disease in the world today. Approximately 270 million people around the world are infected with malaria, about 2 million people die 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 parasites to escape the destructive action of the host immune response against these antigens. In addition, the increase in the speed of NO. Ref. 126043 Malaria infection is due to the spread of strains resistant to chloroquine from Plasmodium faleiparum and other strains resistant to multiple drugs. In the field of animal health, parasitic diseases are a major problem, especially those diseases which are functionally related to malaria. For example, neosporosis is a term used to describe diseases caused by parasites of the Neospora species, especially Neospora caninum, in animals. Neospora infections are known to occur in dogs, cattle, sheep, goats and horses. The final host for Neospora ssp. that include the Neospora Caninum, is unknown and, in addition, the complete cycle of development of the parasite is not understandable. However, the asexual stages of reproduction, known as e squi zogonia, and the behavior of the unicellular tequizoito / baradi zioit stage have been clarified. The tachyzoites are stages of infectious unicellular parasites of about 3-7 X 1-5 mm in size formed after the intracellular endodiogenic reproduction.

Reproduction via tachyzoites preferentially takes place in organelles such as muscle or nerve cells. The pathological symptoms invoked after an infection are associated mainly in those tissues. About five to six weeks after the natural infection in a dog, the symptoms of the disease are caused hyper sensibly by the inflammation of the neuronal cells and the increased tendency to hyperexate the rear legs. The topical lesions are toligatory in the nervous system, preferably in the brain and spinal cord. Extensive non-suppurative inflammations, excrescences and perivascular infiltration of mononuclear cells (macrophage cells, lymphocytes, plasma) dominate, and are also partly apparent in eosinophilis and neutrophilis. In the muscular system, degenerative changes and macroscopically observable necrosis appear. Apart from the atrophy more or less strongly developed, long pale longitudinal stripes are evident. In California and Australia, infections caused by the parasites Neospora Caninum appear to be the main cause of abortion in cattle. The symptoms of the disease in cattle are similar to those presented in dogs. The ataxia is apparent, you can see the reflexes of the joints are weak and the paresis in the hind legs, partially on all four legs. The histological picture is similar to that of dogs, mainly meningitis and non-suppurative myelitis. Data on the activity of the appropriate compounds against neosporosis are rare since the test symptoms continue to develop. Sulfadiazine (administered when drinking water) is effective in experimentally infected mice, only if the treatment is prophylactic, that is, the treatment is initiated before the infection. In dogs, treatment with sulfadiazine and Clindamycin is only successful if it starts at the beginning, that is, when the first clinical symptoms appear as a result of neuron inflammation 1. Coccidiosis, is a small intestine infection, which is relatively rare in humans, which is caused by the parasite Isospora belli. However, humans are also the final host of at least two coccidial species of cyst formation (Sarcicystis suihominis and S. bovihominis). The consumption of improperly boiled or raw pork or beef can lead to severe diarrhea, the cause of which is probably rarely correctly diagnosed. Coccidia (filomym Apicomplexa, Suborder Eimeriina), are one of the most successful groups of parasitic potozoans, which have virtually conquered each class of Metazoa. One of particular importance for men is the 6Q-0Q species that parasitize domestic animals and which in some occasions can cause more severe losses, especially in the poultry, but also sheep, pigs, rabbits and other animals (see Table A). Table A: Causants of intestinal coccidiosis in pets Most pathogenic species are strictly specific hosts. These species have a complex life cycle with two phases of asexual reproduction (ski zogonia or meregonia, and sporogony) and a phase of sexual development (game t ogonia). In view of the greater importance of coccidiosis, numerous reviews are available, for example, by Davies et al., (1963), Hammond and Long (1973), Long (1982, 1990) and Pellerdy (1974). Economically important species sometimes differ considerably in their sensitivity to active medicinal ingredients. The sensitivity of the different stages of development to the medicinal agents also varies enormously. As much as the use of medications is of concern, prophylaxis is the main approach in poultry, where symptoms do not appear until the phase of morbidity is increased, and therapy is the main strategy in mammals (McDougald 1982 ). Polyether antibiotics and sulphonamides, among other medications, commonly they are used for the treatment and prophylaxis. However, the drug resistant coatings of Eimeria have emerged and their resistance to the drug is now a serious problem. The new medications are therefore urgently required. Given the multiplicity of pathogens and hosts, there is no "ideal model" to identify and screen for anticoagulants. For example, most of the substances used to prevent coccidiosis in poultry are insufficiently effective or are completely ineffective against mammalian coccidia (Hoberkorn and Mundt; 1989; Haberkom 1996). Numerous works and instructions have been published in the test of the active ingredients in the animals for anticocadia 1 efficacy, for immunization, etc. A particularly important and understandable example in the study of current methods published by EcKert et al. (1995a). The artemisinin compound, also known as qinghaosu (1), is a tetracyclic 1, 2, 4 - 1 rioxane that occurs in annual Artemisia.

Artemisinin and its derivatives dihydroartemisinin (2), artemether (3) and sodium artesunate (4) are used for the treatment of malaria.

Artemisinin 1 Dihydroartemisinin 2 Artemeter 3 Artesunate sodium 4 Different methods of action have been proposed by various groups to estimate the action of artemisinin and its derivatives in the treatment of malaria (Posner et al., J. Am. Chem. Soc. 1996, 118, 3537; Posner et al. ., J. Am. Chem. Soc. 1995, 111, 5885; Posner et al., J. Med. Chem. 1995, 38, 2273). However, regardless of the current mode of action, all current derivatives suffer from poor oral bioavailability and poor stability (Meshnick et al, Paras itology Today 1996, 12, 79), especially the "first generation" of ethers and esters artemether and sodium artesunate obtained from dihydroartemisinin Extensive chemical studies carried out on artemisinin and the derivatives indicate that a cause of instability is the easy opening of the trioxane radical in artemisinin by itself or in the common metabolite and this occurs when using arteetre and artesunate derivatives, ie dihydroartemisinin. The ring opening will provide the free hydroperoxide, which is susceptible to reduction. The removal of this group ensures the destruction of the activity of the drug with the reduction products that are transformed into deoxo metabolites. In order to make ring opening less easy, the oxygen atom in C-10 can be either removed to provide 10-deoxydihi droa rt emi s in ina, or replaced by other groups, and this provides the basis for the so-called "second generation" compounds which are generally derivatives of 10-deoxiart emisina inina. In addition, derivatives, of artemisinin% have also been prepared with a variety of substituents in C-9. The artemisinin derivatives are also known in the oxygen atom in C-10 which is has replaced by an amino group. For example, Yang et al., (Biorg, Med Chem. Lett, 1995, 5, 1791-1794) has synthesized ten new artemisinin derivatives wherein the oxygen atom in C-10 is replaced by a -NHAr group. where Ar represents a phenyl group, a 3-chloro-phenyl-1-o, 4-chlorophenyl, 3-bromophenol, 4-bromophenol, 4-iodophenyl, 4-methylphenol, 4-methyl-phenyl, -carboxyl feni lo or 4 -carboxi 1 f eni lo. These compounds are tested in vivo for their activity against the K173 strain of Plasmodium berghei and were found to be active. While the current artimisinin derivatives are successful, there are problems associated with stability, bioavailability and potential neuro toxicity. There is also a need for artemisinin derivatives which exhibit a broad spectrum of activity against a variety of parasitoses. It has been found that certain C-10 substituted derivatives of artemisinin are effective in the treatment of diseases caused by infection with a parasite. These compounds are particularly effective in the treatment of diseases caused by infection with a parasite of the genus Pía smodium, Neospora or Eimeria, especially Plasmodium faleiparum, Neospora caninum and Eimeria tenella that cause malaria, neosporosis and coccidiosis respectively. According to the present invention, therefore, a compound of general formula I is provided Or a salt thereof Where Y represents a halogen atom, a group, aryl, C-linked heteroaryl or heterocycloalkyl, optionally substituted cycloalkyl or a group -NR1R2, where R1 represents a hydrogen atom or an alkyl, alkenyl group or optionally substituted alkynyl; R2 represents an alkyl, alkenyl, alkynyl group, optionally substituted cycloalkynyl, aryl or aralkyl; or R1 and R2 together with the interjacent nitrogen atom represent an optionally substituted heterocycle group or an amino group derived from an ester of the optionally substituted amino acid; for use in the treatment and / or prophylaxis of a disease caused by infection with a parasite other than a microorganism of the genus Pia smodium.

Suitable salts include acid addition salts and these can be formed by the reaction of a suitable compound of formula I with a suitable acid, such as an organic acid or a mineral acid. The acid addition salts formed by the reaction with a mineral acid are particularly preferred, especially the salts formed by the reaction with the hydrochloric or hydrobromic acid. The compounds of formula I wherein Y represents a group -NR1R2 where R1 and R2 are as defined previously they are particularly suitable for the formation of the acid addition salts. Any alkyl, alkenyl or alkynyl group unless otherwise indicatedit can be linear or branched and can contain up to 12, preferably up to 6, and especially up to 4 carbon atoms. Preferred alkyl groups are methyl, ethyl, propyl and butyl. It is preferred that any alkenyl or alkynyl group is not an alkenyl-1-alkyl or alkyne-1-one group. In other words, there must preferably be at least one methylene group -CH2- or a similar sp3-hybridized center between a carbon atom that is part of a double or triple C-C bond and the nitrogen atom to which the groups are attached. Preferred alkenyl and alkynyl groups include the propylene, butylene, propynyl and butynyl groups. When an alkyl radical is part of another group, for example the alkyl radical of an aralkyl group, it is preferable that it contains up to 6, especially up to 4 carbon atoms. Preferred alkyl radicals are methyl and ethyl.

An aryl group can be an aromatic hydrocarbon group and can contain from 6 to 24, preferably from 6 to 18, more preferably from 6 to 16, and especially from 6 to 14, carbon atoms. Preferred aryl groups include the phenyl, naphthyl, anthryl, phenanthryl and pyryl groups, especially a phenyl or naphthyl and particularly a phenyl group. When an aryl radical forms part of a group, for example, the aryl radical of an aralkyl group, it is preferred that it be a phenyl, naphthyl, anthryl, phenanthryl, or pyryl radical, especially a phenyl or naphthyl, and particularly a phenyl. An aralkyl group can be any alkyl group substituted by an aryl group. A preferred aralkyl group contains from 7 to 30, in particular from 7 to 24 and especially from 7 to 18 carbon atoms, particularly the preferred aralkyl groups are the benzyl groups, naphthymmethyl, anthocyte, phenanthi It is methyl and pyrilmethyl. A particularly preferred aralkyl group is a benzyl group.

A cycloalkyl group may be any saturated cyclic hydrocarbon group and may contain from 3 to 12, preferably from 3 to 8, and especially from 3 to 6 carbon atoms. Preferred cycloalkyl groups are cyclopropyl, cyclopentyl and cyclohexyl groups. A heteroaryl group may be any monocyclic or polycyclic aromatic ring system containing at least one heteroatom. Preferably, a heteroaryl group is an aromatic ring system provided with 5 to 18 members, particularly provided with 5 to 14 members, especially 5 to 10 members, containing at least one heteroatom selected from the oxygen, sulfur and nitrogen atoms. Preferred heteroaryl groups include the pyridyl, pyrilyl, thiopyrilyl, pyrrolyl, furyl, thienyl, indolinyl, isolindo 1, isolizinyl, imidazolyl, pyridonyl, pyrryl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, purinyl, quinolinyl, and soquinolyl. , quinoxalinyl, pyridazinyl, benzofurani 1 or, ben zoxa zoli lo, and acridinyl. A heteroaryl C-linking group is therefore a heteroaryl group as defined above which is attached to the 1, 2, 4-1 tetracyclic ioxane radical of a compound of general formula I via a carbon atom in the heteroaromatic ring system. A heterocyclic group can be any monocyclic or polycyclic ring system which contains at least one heteroatom and can be unsaturated or partially or totally saturated. The term "heterocyclic" therefore includes heteroaryl groups as defined above as well as non-aromatic het erocyclic groups. Preferably, a heterocyclic group is a ring system provided with 3 to 18 members, particularly 3 to 14 members, especially 5 to 10 members, which contains at least one heteroatom selected from the oxygen, sulfur and nitrogen atoms. . Preferred therapeutic groups include the specific heteroaryl groups mentioned above as well as the pyranyl, piperidinyl, pyrrolidinyl, dioxanyl, pipera zini lo, morpholinyl, thiomorpholinyl, morpholinosul fonyl, t and rahidroisoquinol ini lo and tetrahydrofuranyl. A group tercyclylalkyl can be any alkyl group substituted by a heterocyclic group. Preferably the heterocyclic radical is a heterocyclic group having from 3 to 18 members, particularly from 3 to 14 members, and especially from 5 to 10 members as defined above and the alkyl radical is a C? -6 alkyl group, preferably an alkyl group C? _ And especially methyl. An amino acid can be any a-amino acid such as glycine, alanine, valine, leucine, isoleucine, threonine serine, cysteine, cystine, methionine, aspartic acid, glutamic acid, aspargin, glutamine, lysine, hydroxy 1 is ina, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, hydroxyproline, or phenylglycine and includes both the D- or L- configurations. An ester of the amino acid may be any ester of such an amino acid, alkyl esters, particularly C 1 alkyl esters, the latter being preferred.

When any of the above substituents are designated to be optionally substituted, the substituent groups which are optionally present may be one or more any of those usually in the development of pharmaceutical compounds and / or the modification of such compounds to influence their structure / activity , stability, bioavailability or other properties. Specific examples of such substituents include, for example, halogen atoms, nitro, cyano, hydroxyl, cycloalkyl, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carbonyl, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonate, aryisulfinyl, arylsulphonyl, alkylsulfonate, carbamoyl, alkylamido, aryl, aralkyl, optionally substituted aryl, heterocyclic and heterocyclic alkyl or aryl substituted. When any of the above substituents represents or contains an alkyl or alkenyl substituent group, this may be linear or branched and it can 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. A group or aryl radical can contain from 6 to 10 carbon atoms, phenyl groups are preferred. A heterogeneous group or radical can be a ring system provided with 5 to 10 members as defined above. A halogen atom may be a fluorine, chlorine, bromine or iodine atom and any group which contains a halo radical, such as a haloalkyl group, may therefore contain one or more groups of these halogen atoms. In one aspect it is preferred that Y represents a halogen atom, particularly a fluorine or bromine atom, and especially a fluorine atom. In another preferred aspect Y may represent a C3 cycloalkyl group and an aryl group a C-ring heteroaryl group having 5 to 10 members or a C6-6 alkyl group provided with 5 to 10 members, each group being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxyl groups, C? _4 alkyl, C2_4 alkenyl, C? _4 haloalkyl, C? _4 alkoxy, amino, C? _ alkylamino, di (C? _4) amino amino, carboxyl, aryl Ce-ior occylic groups provided with 5 to 10 and heterocyclic groups of 5 to 10 alkyl C ?- or phenyl substituted members. Preferably Y represents a C6-? S aryl group optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxyl groups, C? - alkyl, C2_4 alkenyl, C? _4 haloalkyl, C? _4 alkoxy, haloalkoxy C ? -4, amino, alkylamino C? _4, di (C1-4 alkyl) to ino, and carboxyl. In particular Y represents a phenyl, naphthyl, anthryl or phenanthryl, each group is optionally substituted by one or more substituents selected from the group consisting of halogen atoms and hydroxyl, methyl, vinyl, C? _4 alkoxy, and carbonyl groups. In a particularly preferred sub-group of compounds, Y represents a phenyl, chlorofenyl, chlorophenyl, bromophenyl, t r ime t ilpheni lo, vinyl phenyl, me t oxi f eni lo group, dimethoxyphenyl, trimethoxy phenyl, carboxyl phenyl, naphthyl, hydroxyl phyl, methoxynaphthyl, anthryl or phenanthryl. Especially preferred are compounds wherein Y represents a phenyl or trimethoxy phenyl group. In a further preferred aspect, Y may represent a group -NR1R2 where R1 represents a hydrogen atom or a C6_6 alkyl group and R2 represents a C6_6 alkyl, C3_8 cycloalkyl, C6_ ?o or C_6 aralkyl aryl, or R1 and R2 together with the interadyacent nitrogen atom represents a heterocyclic group provided with 5-10 members or an amino group derived from a C6-6 alkyl ester of an amino acid, each group is optionally substituted by one or more substituents selected from the group consisting of halogen atoms, C? -4 alquiloalkyl groups, C halo halo haloalkyl, C? _6alkoxycarbonyl, phenyl, halophenyl, C? _4 alkylphenyl, haloalkyl 1-phenyl C C _4, C? _ alco alkoxyphenyl, benzyl, pyridyl and pyrimidyl. In particular, Y can represent a group -NR1R2 where R1 represents a hydrogen atom or a C alquilo _ alkyl group, and R2 represents a C? _4 cycloalkyl C? _4 alkyl group, phenyl or benzyl, or R1 and R2 together with the interadyacente nitrogen atom represents a heterocyclic group provided with 6 to 10 members or an amino group derived from a C? _4 alkyl ester of an amino acid, each group is optionally substituted by one or more substituents selected from a group consisting of halogen atoms, haloalkyl groups C4_4, alkoxycarbonyl C4_4, phenyl, halophenyl, C3_4 alkylphenyl, haloalkyl 1 phenyl C4-4, alkoxyphenyl C3_, benzyl , pyridyl and pyrimidyl. In a particularly preferred subgroup of these compounds, Y represents a propylamino group, cyclopentyllamino, cyclohexylamino, phenylamino, f-chlorophenylamino, chloropheniumlamino, bromofenilamino, iodopheni-1-amino, methoxycarbonyl-1-enylamino, bi-phenylamino, benzylamino, fluorobenzylamino, bis (trifluoromethyl) -benzylamino, phenylethylamino, phenylmet oxycarbonyl, methylamino, diethylamino, morpholinyl, thiomorpholinyl, mor fol i nosu 1 f oni 1, indolinyl, tet rahydro is oqu i no 1 ini 1, phenylpiperazinyl, fluorophenylpiperazinyl, chloro-phenylpiperazyl, methylphenylpiperazinyl, trifluoromethylphenyl, piperazinyl, methoxyphenylpiperazinyl, benzylpiperazinyl, pyridinylpiperazinyl and pir imidini lpipera z ini lo. Especially preferred are compounds wherein Y represents a propylamino, phenylamino, bromofeni 1 amino, io-1-amino, bi-phenylamino, benzylamino, bis (trifluoromethyl) benzylamino, phenylethylamino, phenyl-methoxycarbonylmethyl or morpholinyl group. . Preferably the parasite is an organism of the genus Neospora or of the genus Eimer i a. The present invention also provides the use of a compound of general formula I as defined above for the manufacture of a medicament for the treatment and / or prophylaxis of a disease caused by the infection of a parasite other than an organism of the genus Plasmodium. Preferably the parasite is an organism of the genus Neospora of the genus Eimer i a. Certain compounds of the general formula I are new and the invention therefore further provides a compound of the general formula I as defined above, with the proviso that, when Y is a group -NR1R2 and R2 represents a phenyl group, 3-chlorofeni 1 or, 4-chlorophenyl, 3-bromophenyl, 4-bromo-phenyl, -iodopheni-1, 4-methylphenyl, 4-methyl-1-phenyl, 3-caboxy 1 -f i 1 oo 4-carboxylpheni lo, then R 1 is an optionally substituted alkyl group. It can be seen that the compounds of general formula I are capable of existing as different geometric or optical isomers. The present invention thus includes both individual isomers and mixtures of such isomers. The present invention also provides a process for the preparation of a new compound of the general formula I as defined in the previous paragraph, which comes the reaction of a compound of general formula II. wherein Q represents a hydrogen atom or a t r ime t i i i i lo group, with a suitable halogenating agent to form a compound of the general formula I wherein Y represents an atom halogen; and, if desired, the reaction of the compound of general formula I formed in this way with either a Grignard reagent of general formula YMgX where Y is a cycloalkyl, aryl, C-heteroaryl or heterocyclylalkyl group which is optionally substituted and X is a halogen atom to form a compound of general formula I wherein Y represents a cycloalkyl, aryl, heteroaryl group in C or heterocyclyl heterocycle optionally substituted or with an amine of general formula HNR1R2 where R1 and R2 are as defined above to form a compound of general formula I wherein Y represents a group -NR ^ 'R2 where R1 and R2 are as defined above. Suitable halogenating agents for forming the compounds of general formula I wherein Y represents a halogen atom include diethylaminoa trifluoride trifluoride, chlorotretinoin trifluoride, bromotimetry, and bromide. ti 1 yes tin. In particular, compounds of general formula I wherein Y represents a chlorine, bromine or iodine atom can be prepared by making reacting a compound of general formula II wherein Q represents a trimethyl group with an agent of chlorination, bromination or iodination respectively, such as chlorotrimethylsilane, bromot rimetyllysilane or trimethylamine iodine, respectively . This reaction can be conveniently carried out in the presence of a solvent, suitable solvents include aromatic hydrocarbons, especially chlorinated hydrocarbons, such as dichloromethane. Preferably, the reaction is carried out at a temperature of from -30 ° C to 10 ° C, particularly from -5 ° C to 5 ° C, but is especially preferred near 0 ° C. The compounds of general formula I wherein Y represents a fluorine atom can be conveniently prepared by reacting a compound of general formula II wherein Q represents a hydrogen atom with a suitable fluorinating agent, such as dimethyl uramino trifluoride zuf. re. This reaction can be conveniently carried out in the presence of a solvent, suitable solvents include halogenated hydrocarbons, especially chlorinated hydrocarbons, such as dichloromethane. Preferably the reaction is carried out at -5 ° C to room temperature, this is -5 ° C to 35 ° C, preferably 0 to 30 ° C. the reaction can also be carried out under an inert atmosphere such as nitrogen. Suitable Grignard reagents for forming the compounds of the general formula I wherein Y is an optionally substituted cycloalkyl, aryl, C-linked heteroaryl or heterocyclylalkyl group include compounds of general formula YMgX wherein X represents a chlorine, bromine or iodine atom. However, it is preferred that X represents a bromine atom. The reaction of a compound of general formula I wherein Y represents a halogen atom, preferably a bromine atom with a Grignard reagent can conveniently be carried out in the presence of a solvent. Suitable solvents include the ethers, such as diethyl ether. Preferably, the reaction is carried out under an inert atmosphere, such as nitrogen, at a temperature of -5 ° C to 5 ° C, especially prefer at a temperature of 0 ° C. This method produces a unique pure isomer of the final product. The reaction of an amine with a compound of general formula I wherein Y represents a halogen, preferably a bromine atom to form a compound of general formula I wherein Y represents a group -NR1R2 where R1 and R2 are as defined above may be carried out conveniently in the presence of a solvent. Suitable solvents include halogenated hydrocarbons, especially chlorinated hydrocarbons, such as dichloromethane, and ethers, such as tetrahydrofuran. Preferably, the reaction is carried out at a temperature of -5 ° C to 5 ° C, the temperature of 0 ° C is especially preferred. When a compound of the general formula I in which Y represents a bromine atom further reacts with a Grignard reagent or an amine to form a compound of general formula I wherein Y represents a cycloalkyl, aryl, C-heteroaryl or het-t-group optionally substituted erocyclylalkyl or a group -NR1R2 wherein R1 and R2 are as defined above, it is preferred that the compound of the general formula I in which Y represents a bromine atom is generated i n s i t u by reacting a compound of general formula II wherein Q represents a trimethylsilyl group with the bromot rimet ils ilane. A compound of general formula II in which Q represents a group t rime ti 1 si 1 i 1 or can be prepared by reacting the inartin hydroart, that is, the compound of general formula II where Q represents a hydrogen atom , with chlorine trimet i ls i tin in the presence of a base, such as pyridine or triethylamine. Preferably, the reaction is carried out at room temperature, that is, from 15 to 35 ° C, preferably from 20 to 30 ° C. The innate hydroartemis, that is, the compound of general formula II wherein Q represents a hydrogen atom, is a known compound and can be prepared by known processes. The compounds of general formula I wherein Y represents a cycloalkyl, aryl, C-linked heteroaryl or optionally substituted heterocyclic group may also be prepared by reacting the 9,10-anhydroart emisinin with a compound of general formula Y-H, where Y is as defined above, in the presence of a suitable Lewis acid. This method produces a mixture of isomers in the final product. Suitable Lewis acids include the boron trifluoride dieterate and the trifluoromethanesulfonic acid. The reaction can be conveniently carried out in the presence of a solvent. Suitable solvents include halogenated hydrocarbons, especially chlorinated hydrocarbons, such as dichloromethane. Preferably, the reaction is carried out, at room temperature, that is, from 15 to 35 ° C, preferably from 20 to 30 ° C. The 9, 10 -anhydroart emin sine can be conveniently prepared by reacting the dihydroartemisinin with the anhydro trifluoroacetic. The reaction can conveniently be carried out in the presence of a solvent, preferably a halogenated hydrocarbon, and especially a hydrocarbon chlorinated, such as dichloromethane. It is preferred that the reaction be carried out in the presence of a base, such as pyridine or a derivative thereof, for example, dimethylaminopyridine. Preferably, the reaction is carried out under an inert atmosphere, such as nitrogen, at a temperature of -5 to 5 ° C, preferably at 0 ° C, with the reaction mixture the reaction mixture is allowed to warm to room temperature, that is, from 15 to 35 ° C, preferably from 20 to 30 ° C. The compounds of the general formula I wherein Y represents an optionally substituted aryl or heteroaryl group of C-bond can also be prepared by reacting the 10-tr icloroace tamido i 1-10-deoxoa rt emi s inina with a compound of general formula YH, where Y is as defined above, in the presence of a suitable Lewis acid, such as diethyl ether boron trifluoride. It is preferred that the 10-t ricloroacet imidoi 1-10-deoxoart eminent metal be generated by reacting a compound of general formula II wherein Q represents a hydrogen atom with t ricloroacet onit in the presence of a suitable base, such as 1, 8 -di a zabi ci cio [5. .0] undecano. Preferably the reaction to form the inino-10-t-ricloroacet imido and 1-10-deoxoart is carried out at room temperature, that is, from 15 to 35 ° C, preferably from 20 to 30 ° C. Conveniently carried out in the presence of a solvent Suitable solvents include halogenated hydrocarbons, especially chlorinated hydrocarbons, such as dichloromethane Preferably, the remainder of the reaction is carried out at a temperature of -60 to -20 ° C particularly -55 to -30 ° C, and especially -40 to -50 ° C.

The compounds of the general formula I in which Y represents an optionally substituted aryl group or a C-heteroaryl group can also be prepared by reacting an inino-amyloxy compound in which the acyloxy group is of formula A (C = 0) -O-, wherein A represents an alkyl, cycloalkyl, aryl, aralkyl, heterocyclic or polycyclic optionally substituted group, with a compound of general formula Y-H, where Y is as defined above, in the presence of a suitable Lewis acid. Suitable Lewis acids include diethyl etherate boron trifluoride, tin (IV) chloride, copper (II) trifluoromethyl sulfonate and trifluoromethanesulfonic acid. It is preferred that the Lewis acid be etherate diethyl boron trifluoride. When A represents an optionally substituted alkyl group, unless otherwise indicated, it 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 A represents an optionally substituted aryl group, this may be any aromatic hydrocarbon group and may contain from 6 to 24, preferably from 6 to 18, more preferably from 6 to 16, and especially from 6 to 14, carbon atoms. Preferred aryl groups include the phenyl, naphthyl, anthryl, phenanthryl and pyryl groups, especially those preferred phenyl, naphthyl and anthryl groups. When an aryl radical is part of another group, for example the aryl radical of an aralkyl group, it is preferred that it be a phenyl, naphthyl, anthryl, phenanthryl or pyryl radical, especially a phenyl or naphthyl radical and particularly a phenyl. When A represents an optionally substituted aralkyl group this may be an alkyl group substituted by an aryl group. A preferred aralkyl group contains from 7 to 30, particularly from 7 to 24, more particularly from 7 to 18, and especially from 7 to 10 carbon atoms, particularly the preferred aralkyl groups are benzyl, na ft i lme ti 1 o, anti rilme ti 1, f enan tri-methyl and pyrilmethyl, but especially a benzyl group is preferred. When A represents an optionally substituted cycloalkyl group, this may be any unsaturated or saturated unsaturated hydrocarbon group and may contain from 3 to 12, preferably from 3 to 8, and especially from 3 to 6 carbon atoms. The cycloalkyl groups preferred are the cyclopropyl, cyclopentyl and cyclohexyl groups. When A presents an optionally substituted polycyclic group, this may be any partially or saturated unsaturated hydrocarbon group which contains more than one ring system. Such systems can be "fused", that is, the adjacent rings have two carbon atoms in common, "bridge" that is, the rings are defined by at least common carbon atoms (bridgehead) and at least three chains acyclics (bridges) that connect the common carbon atoms, or "Spiro" compounds, that is, the adjacent rings are joined by a common carbon atom. It can also be seen that the polycyclic group may contain more than one of those types of ring system. The polycyclic groups preferably contain from 4 to 30, particularly from 4 to 26, and especially from 6 to 18 carbon atoms. Bicyclic, tricyclic and tertiary groups are particularly preferred. Preferred bicyclic groups contain from 4 to 14, especially from 6 to 10, carbon atoms. Preferred tricyclic groups contain from 5 to 20 carbon atoms, especially from 6 to 14 carbon atoms, but anti-raquinone groups are preferred. Preferred tetracyclic groups contain from 6 to 26, especially from 6 to 18 carbon atoms. The optional substituents for substituent A can be any of those previously identified as suitable in this respect. The reaction can be conveniently carried out in the presence of a solvent. Suitable solvents include halogenated hydrocarbons, especially chlorinated hydrocarbons, such as dichloromethane. The reaction is preferably carried out under an inert atmosphere such as a nitrogen atmosphere. The reaction is preferably carried out at a temperature of -60 to -20 ° C, particularly -55 to -30 ° C, and especially -40 to -50 ° C.

The compounds of formula I wherein Y represents a substituted aryl group wherein at less one of the substituents is a hydroxyl group can also be prepared by rearranging the corresponding C-10-link artemisinin derivative so that the oxygen atom of the ether bond becomes the oxygen atom of the hydroxyl group in the aryl substituent group of the desired product. Such rearrangement can be effected by reacting the corresponding C-10 ether link artemisinin derivative with the Lewis acid, such as the boron trifluoride dieterate. The reaction is conveniently carried out in the presence of a solvent such as dichloromethane at a temperature of -5 ° C to 5 ° C, preferably at 0 ° C. Certain compounds of general formula can also be prepared by means of the conversion of another compound of general formula I. For example, it can convert 10- (4-vinyl-1-phenyl) -dihydroartemisinin to 10- (4-carboxy-phenyl-1) dihydroa rt emi s inina to react with an oxidation agent, such as potassium permanganate. Also, compounds of general formula I which contain a heterogenous radical that have at least one sulfur atom in the ring system can be oxidized to form compounds of general formula I wherein the or each sulfur atom is converted to a sulfonyl or sulfinyl group by means of the reaction with a suitable oxidation agent. Suitable oxidizing agents include the N-oxide of 4-methyl fluoride (NMO), the tetrapropylammonium perruthenate (TPAP) and mixtures thereof. The reaction can be conveniently carried out in the presence of a solvent, suitable solvents include halogenated hydrocarbons, especially chlorinated hydrocarbons, such as dichloromethane. The reaction is preferably carried out at room temperature that is, from 15 to 35 ° C, preferably from 20 to 30 ° C. the reaction can also be carried out under an inert atmosphere, such as a nitrogen atmosphere.

The invention also provides a pharmaceutical composition which comprises a carrier and, as an active ingredient, a compound new of general formula as previously defined A pharmaceutically acceptable carrier can be any material wherein the active ingredient is formulated to facilitate administration. A carrier can be a solid or a liquid, which includes a material which is normally gaseous but which has been compressed to form a liquid, and any of the carriers normally used in formulations of pharmaceutical compositions can be used. Preferably, the compositions according to the invention contain from 0.5 to 95% by weight of the active ingredient. The compounds of general formula I can be formulated, for example, in tablets, capsules, suppositories or solutions. These formulations can be produced by known methods using conventional solid carriers such as, for example, lactose, starch or talc or liquid carriers such as, for example, water, fatty oils or liquid paraffins. Other carriers that may be used include materials derived from animal or vegetable proteins, such as gelatins, dextrins and soybeans, wheat and psyllium seed proteins; gums such as acacia, guar, agar, and xantan; polis acarids; alginates; ca rbox ime t i celluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinyl pyrrolidones; peptide / protein or polysaccharide complexes such as acacia gelatin complexes; sugars such as mannitol, dextrose; galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicates; and amino acids having from 2 to 12 carbon atoms such as a glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxypro 1 ina, L-isoleucine, L-leucine, and L-phenylalanine .

Auxiliary components such as tablet disintegrants, antiperspirants, preservatives, antioxidants, surfactants, viscosity enhancer, coloring agents, flavoring agents, pH modifiers, sweeteners or flavoring agents can be incorporated in the composition. Suitable coloring agents include red, black and yellow iron oxides and FD & C such as blue FD & C No. 2 and red FD & C No. 40 available from Ellis & Everard. Suitable flavoring agents include peppermint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavorings and combinations thereof. Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid, and maleic acid. Suitable sweeteners include aspartame, acesulfame K and thaumatin. Suitable flavoring-coating agents include sodium bicarbonate, ion exchange resins; Cyclodextrin inclusion compounds, active adsorbates and microencapsules.

For the treatment of and prophylaxis against coccidiosis and related parasites, for instance, in poultry, especially chickens, ducks, geese and turkeys, can be mixed from 0.1 to 100 ppm, preferably from 0.5 to 100 ppm of the Active compound in an appropriate edible material, such as nutrition food. If desired, the applied amounts may be increased, especially if the active compound is well tolerated by the container. In accordance, the active compound can be applied with water to drink. For the treatment of a single animal, for instance, for the treatment of coccidiosis in mammals or t oxoplasmos i s, the amounts of 0.5 to 100 mg / Kg of the body weight of the active compound are preferably administered daily to obtain the desired results. However, this 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 species of animal, and its individual reaction to the drug or class of formulation or the time or interval in which the medication is applied. In special cases, the use of less than the minimum amount given above may be sufficient, while in other cases the maximum dose may tend to be exceeded. For a large dose, it may be convenient to divide the dose into several smaller simple doses. The invention also includes a novel compound of the general formula I as defined above for use in the treatment and / or prophylaxis of a disease caused by infection with a parasite of the genus Plasmodium and the use of a new 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 of the genus Plasmodium. Preferred compounds in this aspect include compounds of the general formula I wherein Y represents a fluorine atom, Y represents a phenyl group, dimethyl oxy phenyl or trimethoxy fyli or Y represents a propylamino group, f 1 uorophenylamine, bifeni 1 amino, benzylamino, f eni le ti lamino, feni ímet oxycarboni ímet i lamino or diethylamino.

The invention provides a method for the treatment of a disease caused by infection with a different parasite an organism of the genus Plasmodium which comprises administering to host in need of said treatment a therapeutically effective amount of a compound of the general formula I as defined above. Preferably, the parasite is an organism of the genus Neospora or of the genus Eimeria. Also provided is a method for the treatment of 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 novel compound of the general formula I as defined above.

In addition, the invention is illustrated by the following examples.

Example 1 Preparation of (lOß-f luoro-10-deoxydihydroartemis inin) of 1 O-fluoro-10-deoxo-10 [ihydro-artemisinin (Formula I: Y = Fj) A solution of dihydroartemisinin (1136 mmol in dichloromethane (24 ml) is added at 0 ° C under nitrogen and diethylaminoazufuretrichloride (DAST) (0.6 ml, 4.8 mmol) is added. The reaction mixture is allowed to warm to room temperature and then stirred under nitrogen for 24 hours.The yellow solution is cooled again to 0 ° C, a solution of a2C3 (5%, 20 ml) is added and the mixture After stirring for 2 hours at room temperature, the two phases are separated and the organic layer is washed with 1 molar HCl, 5% NaHCO3 and water and dried over MgSO4, immediately after evaporation of the solvent, the residue purify twice by flash column chromatography (10% ethyl acetate / hexane), followed by recrystallization from hexane (289 mg, 50. 5%); aH NMR (300 MHz, CDC13): d ppm 0.97 (d, J6_ Me, e = 6.1 Hz, 3 H, 6-CH3), 1.00 (d, J9-Me, 9 = 7.4 Hz, 3 H, 9-CH3), 1.13-1.47 (m, 3H), 1.44 (s, 3 H, 3-CH3), 1.47-1.72 (m, 4H), 1.82-1.96 (m, 2 H), 2.05 (ddd, J = 14.6 Hz, J = 4.9 Hz, J = 3.0 Hz, 1 H), 2.39 (td, J = 13.5 Hz, J = 4.0 Hz, ÍH), 2.64 (dm, J9 H = 36.1 Hz, 1 H, H-9), 5.60 (dd, JÍO-F = 54.4 Hz, J? o.9 = 2.4 Hz, 1 H, H-10), 5.56 (d, J = 1.83 Hz, 1 H, H-12); 19 F NMR (282 MHz, CDC13): d (ppm) = - 136.43 (dd, JF.IO = 54.1 Hz, JF.9 = 36.0 Hz); MS (Cl, NH3): m / z (%) = 304 [M + + NH4 +] (18), 286 [M +], 284 [304-HFJ (100), 267 (64), 256 (28), 239 ( 16), 221 (12), 163 (8), 52 (28).

E j empl o 2 Preparation of (l? ß- (phenyl) (dihydroart emi s inin) of 10β-phenyl-10-deoxo-10-dihydro-artemis inina (Formula I: Y = phenyl) (a) preparation of 10- (t rime t i 1 i i loxi) dihidroart emi s inina (Formula II: Q = -Si (CH3) 3) Method 1 Chlorotrimethylsilane (5.20 ml, mmol) is added dropwise to a solution of dihydroartemisinin (1.51 g, 5.32 mmol) in pyridine (20 ml) at 0 ° C under nitrogen. The mixture is stirred at room temperature for an additional 1 hour and poured into an ice-water mixture. The solution is extracted with diethyl ether (3X15 ml), dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography (Si02; ethyl acetate / 5% hexane) to yield 10- (trimethylsilyloxy) dihydroarticine as a white solid (1.47 g, 78%). dH 5.49 (HH, s, H-12), 5.19 (1 H, d, J = 3.05 Hz, H-10), 2.52-2.62 (HH, m, H-9), 2.39 (1H, ddd, J = 17.5, 13.4, 4.01 Hz), 2.04 (HH, ddd, J = 14.5, 4.84, 3.05 Hz), 1.20-1.97 (9H, m), 1.45 (3H, s, H-14), 0.97 (3H, d, J = 6.24 Hz, H-16), 0.87 (3H, d, J = 7.29 Hz, H-15), 0.17 (9H, s, (CH3) 3Si). Method 2 - - Preparation of 10a- (t-rimeyl siloxy) dihydroart e in sine (Formula II: Q = -Si (CH3) a) Triethylamine (0.94 ml, 6.65 mmol) and chlorot rime ti 1 s ilane (0.84) are added dropwise. ml, 6.65 mmol) was added to a solution of dihydroartemisinin (1.51 g, 5.32 mmol) in dichloromethane (40 ml) at 0 ° C under nitrogen. The mixture is stirred at room temperature for an additional 1 hour and poured into an ice-water mixture. The aqueous solution is extracted with dichloromethane (2 × 20 ml). The combined organic layers are dried (MgSO) and concentrated in vacuo. The residue is purified by flash chromatography (Si02, 5% ethyl acetate / hexanes) to give 1 O.a.- (t-trimethyl-isoxy) dihydro-art as inine as a white solid (1.48 g, 78%). eH 5.32 (H, s, H-12), 4.76 (1H, d, J = 9.00 Hz, H-10), 2.25-2.45 (2H, m, H-8, H-9), 2.01 (H, m) , H-4), 1.89 (H, m, H-5), 1.18-1.79 (8H, m, H-2a, H-2b, H-3a, H-3b, H-6a, H-6b, H -7a, H-7b), 1.31 (3H, s, 1-CH3), 0.95 (3H, d, J = 5.88 Hz, 9-CH3), 0.86 (3H, d, J = 7.14 Hz, 5-CH3) , 0.20 (9H, s, Me3Si) ppm. (b) Preparation of (10-bromoa rt emi s inin) of 10-bromo-10-deoxo-10-dihydroartemisinin (Formula I: Y = Br). Triturated dropwise with bromotrimethylsilane (140 μl, 1.06 mmol) a solution of 10α- (trimethylsilyoxy) dihydroartine dihydroart (372 mg, 1.04 mmol) prepared as described in (a) Method 2 above in dichloromethane (5). ml) at 0 ° C. The mixture is stirred at 0 ° C for an additional 30 minutes to produce 10-bromoart emisinin in situ. (c) Preparation of (10β- (pheny1) dihydroart emisine inin) of 10β-phenyl-10-deoxo-10-dihydro-art emin sine (Formula I: Y = phenol). A solution prepared in vacuo is concentrated in (b) previous. The residue is dissolved in diethyl ether (5 ml). To this solution is added iodide magnesium bromide (1400 ml, 2.38 mmol, 1.7 M) at 0 ° C under nitrogen. The mixture is then stirred at 0 ° C and then allowed to reach room temperature overnight. Then the solution is tempered with a chloride solution of - - Saturated onium, dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography (Si02, 8% ethyl acetate / hexanes to produce (1 Oß- (phenyl) dihydroart emission in) of 10β-phenyl-10-deoxo-10-dihydroart inina (159 mg, 45%) as a white solid.Recrystallization of the ether / hexane mixture provides a colorless rectangular crystal, Mp 122 ° C; [] D20 -36.0 ° (C 0.47 / CHC13); vmax (film) 2938, 2874, 1494, 1452, 1376, 1208, 1112, 1076, 1058, 1038, 1010, 954, 944, 904, 882, 852, 820, 740, 700, dH 7.19-7.34 (5H, m, Ar-H), 5.75 (1H, d, J = 6.70 Hz, H-10), 5.60 (HH, s, H-12), 2.71-2.84 (HH, m, H-9), 2.31-2.42 (HH, m), 1.65-2.12 (5H , m) 1.28-1.60 (5H, m), 1.41 (3H, s, H-14), 1.01 (1H, d, J = 5.77 Hz, H-16), 0.54 (1H, d, J = 7.68 Hz , H-15), dc 141.03, 127.67, 126.24, 126.09, 102.22, 90.82, 81.10, 72.99, 51.46, 43.45, 37.46, 36.64, 34.16, 32.08, 25.68, 24.88, 24.71, 19.85, 13.62, m / z (Cl , CH4) 345 (M + 1, 14%), 327 (14), 299 (100), Anal, Cale. For C23H2804: C, 73.26; H, 8.14; Found: C, 73.58; H, 8.32. experiment difference nOe: irradiation of the - doublet signal from H-10 to d 5.75 provides a 10% increase in the multiplet signal from H-9 to d 2.75; this shows that the stereochemistry of H-10 and H-9 are Syn of one another.

Example 3 Preparation of (10a- (4'-fluorobenzylamino) dihydroart emisinin) of 10a- (4'-fluorobenzylamino) -10-deoxo-10-dihydroarte isinin (Formula I: Y = -NR ^ 2, R1 = RH, R2 = 4-F benzyl). (a) Preparation of 10a- (trimet i lsi) dihydroart inina emission (Formula II: Q = -Si (CH3) 3) • Triethylamine (0.94 ml, 6.65 mmol) and chlorot rimet ilsilane (0.84 ml, 6.65 mmol) are added dropwise to a solution of dihydroartemisinin (1.15 g, 5.32 mmol) in dichloromethane (40 ml). ) at 0 ° C under nitrogen. The mixture is stirred at room temperature for an additional 1 hour and poured into an ice-water mixture. The aqueous solution is extracted with dichloromethane (2 × 20 ml). The combined organic layers are dried (MgSO4) and concentrated in vacuous The residue is purified by flash chromatography (Si02, 5% ethyl acetate / hexanes) to yield 10a- (trimethylsiloxy) dihydroartemisinin as a white solid (1.48 g, 78%). dH 5.32 (HH, s, H-12), 4.76 (HH, d, J 9.00 Hz, H-10), 2.25-2.45 (2H, m, H-8, H-9), 2.01 (HH, m, H-4), 1.89 (HH, m, H-5), 1.18-1.79 (8H, m.H-2a, H-2b, H-3a, H-3b, H-6a, H-6b, H- 7a, H-7b), 1.31 (3H, s, 1-CH3) 0.95 (3H, d, J 5.88 Hz, 9-CH3), 0.86 (3H, d, J 7.14 Hz, 5-CH3), 0.20 (9H , s, Me3Si) ppm. (b) Preparation of (10a- (4'-f luoro-benzyllamino) dihydroartemisinin) of 10a- (4-fluorobenzylaraine) -10-deoxo-10-dihydroartic acid (Formula IY -NR R2 Rx = HR¿ = 4-F-benzyl) It is treated dropwise with bromot rimethe 1 if tin (80 μl, 0.600 mmol) to a solution of 10a- (t rime ti Is i loxi) dihydroart e in sine (214 mg, 0.600 mmol ) prepared as described in (a) above in dichloromethane (5 ml) at 0 ° C. The mixture is stirred at 0 ° C for an additional 30 minutes which is then transferred through a tube in a solution of 4- fluorobenzylamine (140 μL, 1.20 mmol) in tetrahydrofuran (5 mL) at 0 ° C. The mixture is stirred at 0 ° C and then allowed to reach room temperature overnight. The suspension is washed with a NaHCO3 solution, dried (MgSO) and concentrated in vacuo. The residue is purified by flash chromatography (Si02; 15% ethyl acetate / hexanes) to produce 10a- (4'-fluorobenzylamino) -10-deoxo- (10a- ('-f luorobenzylamino) -dihydroart ein s inin). 10-dihydroartemisinin (76.9 mg, 33%) and (9, 10 -anhydro-dehydroart emi s inin) of 9, 10-anhydro-10-deoxoa rt emi without ina (84.7 mg, 53%), both as white solids. P.f. 45.2-46.3 ° C; [a] D20 -18.2 ° (c 0.055 CHC13); dH 7.32-7.37 (2H, m, Ar-H), 6.95-7.02 (2H, m, Ar-H), 5.29 (H, s, H-12), 4.10 (H, d, J = 13.8 Hz, H -l '), 4.08 (ÍH, d, J = 9.76 Hz, H-10), 3.91 (1H, d, J = 13.8 Hz, Hl'), 2.33-2.42 (2H, m,), 1.85-2.07 ( 3H, m), 1.65-1.77 (2H, m), 1.03-1.75 (5H, m,), 1.46 (3H, s, H-14), 0.96 (3H, d, J = 6.02 Hz, H-16) , 0.93 (3H, d, J = 7.19 Hz, H15); dc 136.42 (d, J = 3.10 Hz), 129.30 (d, J = 7.9 * 7 Hz), 114.75 (d, J = 21.1 Hz), 103.90, 91. 35, 85.47, 80.60, 51.66, 47.50, 45.82, 37.23, 36.26, 34.03, 32.72, 26.03, 24.61, 21.70, 20.15, 14.06; dF -118; m / z (Cl, CH4) 392 (M ++ 1, 90%), 374 (54), 346 (100), 328 (20), 267 (16), 209 (16), 165 (26), 109 (18) Anal. Cale. For C22H3oN04F: C, 67.50; H, 7.72; N, 3.58; Found: C, 67.51; H, 7.77, N, 3.49.

EXAMPLE 4 Preparation of 10- (2 ', 4'-dimethoxyphenyl) -10-deoxo-10-dihydroartemis inine (10 - (2', 4 '-dimet oxy-phenyl-1) dihydro-art emin sine (Formula I: Y = 2, 4-dimethoxy f eni 1) (a) preparation of (9, 10 -anhydroart emi s inin) of 9,10-anhydro-10-deoxoartemisinin is added to a solution of dihydroartemisinin (500 mg, 1.86 mmol) in dichloromethane (28 ml) at 0 ° C under nitrogen 4 - (N, N-dimethylamino) pi r idine (37 mg) and trifluoroacetic trifluoride anhydride (0.79 ml, 5.58 mmol). The mixture is allowed to warm to room temperature and is stirred overnight. The solution is then concentrated in vacuo. The residue is purified by fast chromatography (Si02; ether: hexane from 0.5: 9.5 to 1.5: 8.5) to produce (9,10) -anhydroartemi s inin) of 9, 10 - anh idro- 10 -deoxoartemi s inina (180 mg, 25%) as a white solid. P.f. 100 ° C; [a] D20-5 + 155.74 ° (c. 0.0101 in CHC13) vmax (film): 2948, 2922, "2862, 2850, 1684, 1432, 1372, 1334, 1198, 1178, 1158, 1142, 1114, 1078, 1028.1016, 992, 954, 944, 904, 880, 828, 812; dH: 6.18 (1H, s, H-10), 5.54 (lh, s, H-12), 2.40 (1H, ddd, J = 17.1, 13.2, 4.14 Hz, H-9), 2.00- 2109 (2H, m), 1.88-1.95 (HH, m), 1.07-1.73 (8H, m), 1.58 (3H, d, J = 1.37 Hz, H-16), 1.42 (3H, s, H-14) ), 0.98 (3H, d, J = 5.98 Hz, H-15), m / z (El): 380 (M +), Anal, Cale. For: C? 5H2204: C, 67.67; H, 8.27; Found: C, 67.63; H, 8.51. (b) Preparation of (10- (2 ', 4'-dimethoxy-phenyl) -dihydroartemis inin) 10- (2', 4'-dimethoxyphenyl) -10-deoxo-10-dihydroartem sine (Formula I: Y = 2,4-dimethoxyphenyl). It is added to a solution of (9.10 anhydroart emisin inin) of 9, 10-anhydro-10 deoxoartemi s inina (191 mg, 0.71 mmol) prepared as described in (a) above and 1,3-dimet oxybenzene (130 μl, 1.00 mmol) in dichloromethane (10 ml) at room temperature under nitrogen, diethyl ether boron trifluoride (2 drops) The solution is stirred for an additional 1 hour and then quenched with a 20% hydrochloric acid solution (5 ml). The mixture is extracted with diethyl ether (3 x 20 ml), and the ether extracts are dried (MgSO 4) and concentrated in vacuo. The residue is purified by flash chromatography (Si02, 15% ethyl acetate / hexanes) to yield (10-2 2 ', 4'-dimethoxyphenyl) of 10 - (2', 4 '-dimet oxy 1) - 10-deoxo-10-dihydroart was inina (89.5, 44%) as a white solid. dH 7.56 (2h, BRD, j = 8.4 Hz, Ar-H), 6.40-6.58 (2H, m, Ar-Hl, 5.43 (H, s, H12), 5.42 (H, s, H-12 '), 5.16 (ÍH, d, J = 10.8 Hz, H-10), 4.96 (1H, d, J = 10.3 Hz, H-10 '), 3.82, 3.78 (Orne), 2.37-2.48 (2H, m), 1.05 -2.07 (10H, m), 1.63 (3H, s, H-14), 1.34 (3H, s, H-14 '), 1.00 (3H, d, J = 6.22 Hz. H - 16'); 0.90- 0.93 (3H, m, H-15 &H-16); 0.59 (3H, d, J = 7.22 Hz, Hl 5 '); m / z (Cl, NH3) 422 (M + NH4 +, 26%), 406 (84), 405 (M ++ 1, 54), 389 (80), 359 (100), 330 (30), 317 (40), 300 (14). Anal. Cale. For C23H3206: C, 68.29; H, 7.97%; Found: C, 68.34; H, 8.09.

Example 5 Preparation of 10a- (2'-hydroxy-1'-naphthyl) dihydroartemis inine (Formula Y = 2-OH naphthyl (a preparation of lOß- (2 r -naf toxi) dihydroartemisinin It is added to a solution of dihydroartemisinin (586 mg, 2.00 mmol) and 2-naphthol (288 mg, 2.00 mmol) in tetrahydrofuran (10 ml), triphenylphosphine (524 mg, 4.00 mmol) and diethyl azodicarboxylate (330 μl 2.00 mmol). at 0 ° C under nitrogen. The mixture is stirred at room temperature overnight. The yellow solution is concentrated in vacuo and the residue is purified by flash chromatography (SiO2, 5% ethyl acetate / hexanes) to produce 10%. - - (2'-naphthyloxy) dihydroart is inina (185 mg, 23%) as a white solid. (b) Preparation of 1 Oa- (2 '-hydroxy-1' -na f t i 1) -dihydroartemis inine. Boron trifluoride dieterate (220 μl) at 0 ° C is added to a solution of 10β- (2'-naphthoxy) dihydroart amine (232 mg, 0.564 mmol) prepared as described in (a) above in dichloromethane ( 10 ml). The mixture is allowed to warm to room temperature and is stirred for an additional 30 minutes. The solution is washed with a 10% sodium hydrogen carbonate solution (2 x 5 ml), dried (MgSO 4) and concentrated in vacuo. The residue is then purified by flash chromatography (Si02; 10% ethyl acetate / hexanes) to yield 1 Oa- (2'-hydroxy-1'-naphthyl) -dihydroartemisinin as a white solid (72.7 mg). dH 8.91 (1H, s, OH), 7.28-7.91 (6H, m, Ar-H), 5.57 (H, s, H-12), 3.11-3.19 (H, m), 1.28-2.55 (11H, m ), 1.51 (3H, s, H-14), 1.04 (3H, d, J = 5.96 Hz, H-16), 0.63 (3H, d, J = 7.23 Hz, H-16).

Example 6 Preparation of (10a- (t iomor folino) di hidroart emi s inin) of 10a- (4'-thiomorpholino-1'-yl) -10-deoxo-10-dih idroart emi s inina (Formula I : Y = t iomorfolino) The reaction of bromide prepared from 10a- (tr imet il-siloxy) dihydroart emin sine (356 mg, 1.00 mmol) as described in example 3 (b) above with thiomorpholine (300 μl, 3.00 mmol) gives the 1 O- (t iomor fol ina) -dihidroartemi sinina (243 mg, 66%) as a white solid after rapid chromatography (8% ethyl acetate / hexanes). P.f. 147. 0-147.6 ° C; [a] D20 + 17 ° (c 0.021 / HCC 13); vmax (film) 2924, 2872, 1454, 1418, 1376, 1326, 1278, 1226, 1198, 1184, 1154, 1130, 1100, 1056, 1038, 1018, 988, 940, 926, 880, 850, 828, 756; dH 5.23 (ÍH, s, H-12), 3.93 (1H, d, J = 10.21 Hz, H-10), 3.20-3.28 (2H, m), 2.85-2.93 (2H, m), 2.53-2.68 ( 5H, m), 2.25-2.36 (HH, m), 1.93-2.01 (HH, m), 1.78-1.86 (1H, m), 1.63-1.70 (2H, m), 1.14-1.52 (5H, m), 1.36 (3H, s, H-14), 0.90-1.04 (HH, m), 0.91 (3H, d, J = 6.14 Hz, H-16), 0.76 (3H, d, J = 7. 18 Hz, H-15); dc: 103.70, 92.28, 91.42, 80.11, 51.54, 50.39, 45.66, 37.19, 36.14, 34.12, 28.15, 25.84, 24.59, 21.44, 20.15, 13.41; m / z (Cl, NH3) 370 (M + + l, 100), 324 (70), 310 (10): Anal. Cale. For C19H31NO4S: C, 61.76; H, 8.46; N, 3.79%; Found: C, 62.04; H, 8.39; N, 3.65.

Example 7 Preparation of 10a- (4'-morpholino-sulfonyl) dihydroartemis inin) of 10a- (4 '- (S, S-dioxo-t-iomorj: ol-1'-yl) -10-deoxo-10-dihydroartemisinin ( formula I_ Y = (4 -mor folinosulfoni 1) of 4 '- (S, S -dioxot i omor f olin- 1' -il) • Add to a solution of (1 Oa- (ti omor fo 1 ino) - dihydroart emi s inin) of 1 O- (4'-t-fluorine) -10-deoxo-10-dihydroart e in sine (388 mg, 1.05 mmol) prepared as described in Example 6 above in dichloromethane (10 ml ) at room temperature under nitrogen, NMO (369 mg, 3.15 mmol), triturated on a molecular sieve (525 mg, 4 Á), and TPAP (18.5 mg, cat.) The mixture is stirred at room temperature - - The whole night atmosphere is then filtered through a pad of Si02 and the residue is washed with ethyl acetate (3 x 15 ml). The filtrate is concentrated in vacuo. The residue is then purified by flash chromatography (SiO2, 35% ethyl acetate / hexanes) to yield (10a- (4'-morpholinosul foni 1) -dihydroart eins inin) of 10a- (4 '- (S, S-dioxothiomorpholinyl-l) -10-deoxo-10-dihydroartemisinin As a white solid (421 mg, 100%), Mp 152.3-152.7 ° C; [a] D20 + 13 ° (c 0.035 / HCCl3); (film) 2928, 2872, 1454, 1378, 1308, 1270, 1228, 1198, 1124, 1040, 1018, 976, 940, 878, 846, 826, 752, 704, 666, dH: 5.27 (H, s, H -12), 4.21 (HH, d, J = 10.30 Hz, H-10), 3.18-3.46, (8H, m), 2.54-2.62 (HH, m), 2.28-2.36 (HH, m), 1.20- 2.02 (9H, m), 1.35 (3H, s, H-14), 0.92-1.06 (ÍH, m), 0.93 (3H, d, J = 5.99 Hz, H-15), 0. 7 3H, J = 7.13 Hz H-16 174.20, 104.09, 91. 92, 90.84, 90.04, 51.74, 51.27, 46.88, 45.46, 37. 29, 36.02, 34.04, 28.91, 25.76, 24.66, 21.45, . 10, 13.31; m / z (Cl, NH3) 402 (M + + l, 100), 373 (30), 356 (64), 342 (16), 356 (20); anal. Cale.

For C19H3? N06S: C, 56.84; H, 7.78; N, 3.49; Found: C, 56.83; H, 7.82; N, 3.37.

Example 8 Preparation of 1 Oa- (4'-benzylpiperazin-1'-i1) -10-deoxo-10-dihydroart in ein (Formula I: Y = 4 '-benzyl-1'-piperazinyl) The reaction of bromide prepared from 10a- (t rime ti 1 -siloxy) dihydroa rt emi s inina (356 mg, 1.00 mmol) as described in example 3 (b) above with 1-benzylpiperazine (212.1 μl, 1.22 mmol ) gives the 1-O- (4'-benzyl-1-piper-az-1 '-i 1) -10-deoxo-10-dihydroart in eine (144.3 mg, 40%) as a white solid, then rapidly chromatograph ( 40% ethyl acetate / hexanes). P.f. 105-106 ° C; [a] D20 + 10.3 ° (c 0.909 / HCC13); vmax (film): 2954, 2920, 2860, 2802, 1494, 1454, 1376, 1344, 1294, 1270, 1204, 1132, 1114, 1062, 1042, 1016, 986, 942, 924, 880, 852, '824, 738, 694 cm "1; 1 h NMR (300 MHz, CDC13) dH 7.43-7.30 (5H, m, Ar-H), 5.35 (1H, s, H12), 4.10 (/ H, d, j = 10.2 Hz , H-10), 3.62 (ΔH, d, J = 13.1 Hz, benzyl-H), 3.55 (1H, d, J = 13.1 Hz, benzyl-H), 3.11-3.06 (2H, m), 2.80-2.70 (2H, m), 2.70-2.30 (7H, m), 2.15-2.02 (ÍH, m), 2.02-1.85 (ÍH, m), 1.85-1.70 (2H, m), 1.70-1.20 (9H, m), 1.20-1.00 (4H, m), 0.88 (3H, d, J = 7.2 Hz, 6-methyl) ppm; 13C NMR (76 MHz, CDC13) of 138.3, 129.13, 128.1, 126.9, 103.8, 91.6, 90.4, 80.3, 63.1, 53.5, 51.7, 45.9, 37.4, 36.3, 34.3, 28.5, 26.0, 24.8, 21.6, 20.3, 13.4 ppm; MS (Cl, CH4) m / e 443 (M ++ l, 10). Anal. Cale. For C26H38N204: C, 7056; H, 8.65; N, 6.33; found: C, 70.24; H, 8.67; N, 6.28.

Example 9 Preparation of 10a- (2'-furyl) -10-deoxo-10-dihydroartemisin (Formula I: Y = 2-furyl). Method 1: It is added to a solution of dihydroartemisinin (284 mg, 1.0 mmol) in dichloromethane (10 ml) at 20 ° C, tri-cycloacetylene tri (2.0 ml, 20.0 mmol) and a drop of 1.8- di a zabi cycle [5.4.0] undecane. The mixture is stirred at 20 ° C for 2 hours then concentrated in vacuo to ° C. The residue is then taken in dichloromethane (10 ml) at 0 ° C and cooled to -40 ° C. The solution is treated sequentially with furan (1.09 ml, 15.0 mmsl), and diethyl ether boron trifluoride (123 μl, 1.0 mmol), and the resulting mixture is stirred at -40 ° C for another 30 minutes. The mixture is quenched with a saturated NaHCO 3 solution and extracted with dichloromethane (2 x 10 ml). The extracts are dried (MgSO4) and concentrate in vacuo. The residue is purified by flash chromatography (SiO2, 15% ethyl acetate / hexanes) to yield the title compound (11.0 mg, 3.3%) as a colorless oil. The analytical sample is obtained from the recrystallization of hexanes.

Method 2: (a) Preparation of (10-dihydroartemisinyl benzoate) of 10 ß-benzyl 1-oxy-10-dihydroartic acid.

It is added to a solution of dihydroartemisinin (586 mg, 2.00 mmol) and benzoic acid (244 mg, 2.00 mmol) in tetrahydrofuran at 0 ° C under nitrogen, triphenylphosphine (524 mg, 2.00 mmol) and - - diethyl azodicarboxylate (ml). The mixture is allowed to warm to room temperature and is stirred overnight. The solution is concentrated in vacuo. It is chromatographed rapidly (Si02, 10% ethyl acetate / hexanes) to produce 1 Oß-dihydroartem benzoate as a white solid (419 mg, 53%). P. f. 151.4-153.0 ° C; [a] D20 + 119 ° (c 0.19 / HCC13); vmax (film): 2942, 2872, 1724, 1452, 1378, 1268, 1176, 1114, 1064, 1024, 976, 902, 858, 832, 754, 712; dH 7.43-8.03 (5H, m, Ar-H), 6.52 (HH, d, J = 3.43, H-10), 5.58 (1H, s, H-12), 2.91-3.01 (HH, m, H- 9), 2.42 (ÍH, ddd, J = 17.4, 13.3, 3.91 Hz), 1.33-2.10 (10H, m), 1.45 (3H, s, H-14), 1.02 (3H, d, J = 6.11 Hz, H-15), 0.98 (3H, d, J = 7.35 Hz, H-14); dc: 165.31, 133.03, 123.96, 129.48, 128.39, 104.30, 95.29, 88.66, 88.63, 80.42, 52.27, 43.84, 37.44, 36.10, 34.43, 29.98, 25.78, 24.50, 24.25, 20.14, 12.50; m / z (El): 388 (M +). (b) preparation of 1 Oa- (2'-f uryl) -10-deoxo-10 dihydroarthene (Formula I: Y = 2-furyl).

- - Sequentially treated with furan (542 μl, 7.5 mmol) and boron trifluoride diethyl ether (123 μl, 1.0 mmol) a solution of 1 Oß-benzylloxy-1 O-dihydroartemisinin (193 mg, 0.50 mmol) in dichloromethane ( 5 ml) at -45 ° C. The resulting mixture is quenched with saturated NaHC 3 solution and extracted with dichloromethane (3 x 10 ml). The extracts are dried (MgSO 4) and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, ethyl acetate / hexanes) to yield the title compound (53.7 mg, 32%) as a colorless oil. P. f. 96-97 ° C; t H NMR (300 MHz, CDC13) dH 7.38 (1H, m, H-5 '), 6.34-6.30 (2H, m, H-3' &H-4 '), 5.38 (H, s, H- 12), 4.46 (ÍH, d, J = 10.9 Hz, H-10), 2.84 (1H, m), 2.60-2.20 (2H, m), 2.20-1.20 (9H, m), 1.20-0.80 (6H, m), 0.62 (3H, d, J = 7.2 Hz, 6-methyl) ppm; 13C NMR (76 MHz, CDC13) of 153.2, 142.0, 110.0, 108.3, 104.2, 92.2, 80.4, 76.6, 71.1, 52.0, 45.7, 37.4, 36.3, 34.1, 31.5, 26.1, 24.7, 21.3, 20.3, 13.7 ppm; MS (Cl, CH4) m / e 335 [M + + l, 43).

- - Example 10 Preparation of 1 Oa- (pyrrol-2'-yl) -10-deoxo-10-dihydroartemisinin (Formula I: Y = 2-pyrrolyl). Sequentially treated with pyrrolo (624 μl, 9.00 mmol) and boron trifluoride diethyl etherate (332 μl, 2.70 mmol) a solution of 10 β-benzyloxy-10-deoxoartemis inine (700.8 mg, 1.80 mmol) prepared as described in Example 9, Method (2) in dichloromethane (30 ml) at -50 ° C, and then stirred at -50 ° C for 1 hour. The mixture is quenched with a saturated NaHCO 3 solution, and extracted with dichloromethane (3 x 10 ml). The extracts are dried (MgSO 4) and concentrated in vacuo. The residue is purified by flash chromatography (Si02; 30% diethyl ether / hexanes) to yield the title compound (486.6 mg, 81%) as a colorless oil. [a] D20 + 198.7 ° (c 0.105 / HCC 13); vmax (film): 2924, 2854, 1460, 1376, 1066, 1024, 722 cm "1; 1 H NMR (300 MHz, CDC13) dH 8.80 (OH, br s, NH), 6.71 (OH," m, H- 5 '.}., 6.04 (2H, m, H-3' &H-4 '), 5.39 (H, s, H-12), 4.47 (1H, d, J = 10.8 Hz), 2.58 (H) , m), 2.50-2.10 (2H, m), 2.10-1.95 (ÍH, m), 1.93 - - (1H, m), 1.80-1.68 (2H, m), 1.68-1.15 (7H, m), 1.15-0.80 (4H, m), 0.93 (3H, d, J = 7.1 Hz, 6-methyl) ppm; 13C NMR (76 MHz, CDC13) of 129.9, 117.6, 107.2, 106.7, 104.1, 91.9, 80.5, 71.9, 60.2, 51.8, 45.7, 37.2, 36.2, 34.0, 32.9, 25.9, 24.6, 21.2, 20.1, 14.0, 13.9 PPM; MS (Cl, butane) m / e 334 (m ++ l, 100). Anal. Cale. For C? 9H27N04: C, 68.44; H, 8.16; N, 4.20; Found: C, 68.77; H, 8.56; N, 3.85.

EXAMPLE 11 Preparation of the iodide salt of 10a- (4'-benzyl-4-β-netylpiperazinium-1'-yl) -10-deoxo-10-dihydroartic acid dihydroart (Formula I: Y = 4 '-benz 1-4 '-me t ilpiperazinium- 1' -yl). The solution is treated dropwise with iodomethane (36.7 μl, 0.59 mmol) with a solution of 1 O- (1-benzylpipe ra z in-1 '-yl) -10-deoxo-10-dihydroart inina (272 mg, 0.62 mmol) prepared as described in Example 8 above in a mixture of dichloromethane (1.8 ml) and diethyl ether (5.4 ml) under a nitrogen atmosphere at 0 ° C. the mixture is stirred and left warm at 20 ° C gradually all night. The precipitate is collected and washed with diethyl ether (2 x 5 ml) and dried under high vacuum. It is further purified by recrystallization from methanol / diethyl ether to produce crystals in rectangular dish form (87 mg, 24%). P. f. 159-161 ° C; [a] D20 + 18.4 ° (c 0.436 HCC13); vmax (film): 3448, 2928, 2196, 1457, 1378, 1210, 1133, 1099, 1041, 982, 918, 880. 852, 828, 766, 732, 642 cm "1; 1R NMR (300 MHz, CDCI3) aH 8.00-7.60 (2H, d, J = 6.2 Hz, H-2"&H-6"), 7.60-7.35 (3H, m, Ar-H), 5.32 (H, s, H-12), 5.25-5.05 (2H; m, benzyl-H), 4.13 (H, d, J = 10.2 Hz, H-10), 3.95-3.55 (4H, m), 3.55-2.90 (9H, m), 2.65-2.20 (2H, m), 2.20-1.15 (14H, m), 1.15-0.87 (4H, m), 0.80 (3H, d, J = 6.9 Hz, 6-methyl) ppm; 13C NMR (76 MHz, CDCl3) ac 133.4, 130.6, 129.1, 126.5, 104.0, 91.5, 90.1, 80.1, 67.4, 59.5, 59.3, 51.5, 45.5, 37.2, 36.1, 34.0, 28.4, 25.9, 24.5, 21.5, 20.1, 13.3 ppm.

Examples 12 to 61 For processes similar to those described in Examples 1 to 11 above, the additional compounds according to the invention are prepared as detailed in Table I below. In this table, the compounds are identified by the reference to Formula I.

Table I > t- > L? s, ~ -I s.) I -J OO or Ct) t- O) O) OR) 00 OR) OR? OR Ex. No. R 'Physical data 53 4-Fluorophenyl White solid P.f 133.6-134.8' C; la) t "- (iosß-isomero) 35.66» (e 0.83, CHC1,); dr: -11B.00; IR (pure) vm: 2952, 2873, 1604, 1510, 1452, 1376, 1222, 1110, 1040 , 1010, 944, 906, 882, 838, 782; d »! 7.29-7.24 < 2H, m, Ph), 7.04-6.97 (2H, m, Ph), 5.70 (H, d, H-10, Cf -6.70 Hz), 5.55 (HH, a, H-12), 2.77-2.6S <1H, m), 2.39-2.28 <1H, m), 2.10-1.97 (2H, ra), 1.90-1.82 ( ÍH,), 1.78-1.64 (2H, m), i.9-1.17 (8H, m), 0.99 (3H, d, 6-Me, J »5.7S Hz), 0.48 (3H, d, 9-Me , J-7.6ß Hz), of 16216.10.10 (d, Ph, Jct-244.0 Hz), 137.42 (d, Ph, JCT «3.09 Hz), 128.30 (d, Ph,," 'T.Bi Hz), 115.16 (d, Ph, JCT »21.27 Hz), 102.92, 91.55, 81.75, 73.15, 52.09, 44. OS, 38.14, 37.30, 34.82, 32.78, 26.35, 25.57, 25.42, 20.52, 10 14.29; MS (Cl positive NH, ) m / z: 382 (MNH, \ 2 X "C, 4 *), 381 (MNH, *," C, 25 *), 380 (MNH, \ base base), 363 (MH \ 6 *); Anal Caled, for C-, H "0, FC 69.59, H 7.51; Find C 69.51, H 7.62. lt » I heard --J OJ Example 62 The parasiticidal activity of the compounds of the invention is investigated by means of the following tests.

Abbreviations used in the examples: C02 = carbon dioxide DMSO = dimet i lsulfoxide ED = line of skin cells of a horse EDTA = acid et ilenodiaminat et raace tico FCS = fetal calf serum RPMI = growth medium for culture of cells Rpm = revolutions per minute VERO = African green monkey kidney cell line (a) Selection of compounds against Caninum Neospora in vitro cell cultures.

The selection 'is conducted in 96-well plates (Falcon 3872). A monolayer of host cells (VERO or ED) are placed on a plate of cell culture. The uninfected monolayers of cells are grown in two 50 ml tissue culture bottles (50 cm3 cell culture area). The cell layer is separated with EDTA-1 rips ina (5 ml Gibco 45300-019) in a C02 culture in a cabinet at 37 ° C. After 10 minutes, more cells are separated. The cells are transferred with a 5 ml pipette into a 50 ml centrifuge tube (Greiner, B769331) containing about 1 ml of wet fetal calf serum. After centrifugation for 5 minutes at 1500 rpm (Varifuge 3.0, Heraeus), the liquid is removed and the cell pill suspended in the RPMI medium (100 ml, RPMI 1640 at 95%, FCS at 2%, L-glu 1% anamin, 1% sodium hydrogen carbonate penicillin / 1% streptomycin). The cell suspension is pipetted in six 96-well plates at 150 μl per well. The coated cell culture plate is placed in an incubation cabinet at 37 ° C under 5% C02 for 24 hours. The cells are then infected with taczoites of Neospora caninum at a concentration of 48,000 taczoites- per well. This is followed by incubation at 37 ° C under 5% C02 for 24 hours. The tested compounds (0.5 - 1.5 mg) are weighed Eppendorf container and dissolved in 1 ml of dimethyl sulfoxide, which corresponds to the dilution of about 1 X 10"3 g mi-1 .The medium used for an additional dilution consists of of 87% RPMI 1640, 10% FCS, 1% L-glutamine, 1% sodium hydrogen carbonate, 1% penicillin / streptomycin In the first selection, concentrations of 10"5, 10" are used and 10 g ml The diluted preparations are then transferred to the cell culture plates at a volume of 150 μl per well after 24 hours of infection with Neospora caninum For the first row, the untreated medium is used, this row contains infected and uninfected cells as controls.The cell plate is incubated at 37 ° C under 5% C02 for 5 days.The microscopic evaluation is conducted for 4 days after treatment and 5 days after infection at an increase of 25 days. X 10 in a Inverse microscope according to the following evaluation scheme.

Evaluating Effect observable 0 = no effect The monolayer completely destroyed 1 = weekly effect The monolayer partially destroyed, groups of parasites can be seen 2 = maximum effect The monolayer intact, without observable tacizoites T = cytotoxic Cells die, des t ruida s The results are shown in Table II below.

Table II (b) Selection of compounds against the cultures of the Eimeria Tenella cell in vitro The kidney cells of 19-day-old chickens are cultured as monolayers in 96-well plates (Falcon 3872) in a medium of skeletons of lactulose hydrosylate. , 5% fetal calf serum, 1% glutamine and 1% non-essential amino acids. After 2 days at 42 ° C under 5% C02, the culture becomes infected with sporozoites extirpated from Eimeria tenella to about 30.00 per well. The tested compounds are dissolved in DMSO and diluted with a culture medium to a maximum final concentration of 10 μl ml "1. The dilution steps are 1:10.On one day 5 post-infection, the cultures are evaluated under a microscope in an increase of 100 folds and the condition of the host cells and the amount of intact schizonts and free merozoites is determined.The efficacy is given as follows: The results are shown in Table II aba j or Table III (c) In vitro selection against Plasmodium flaciparum Two strains of parasites - 2 resistant to chloroquine, and sensitive D6 to chloroquine but resistant to mefloquinine are used. In Table IV below, the best compounds should - - show uncrossed resistance between the two strains. The assay depends on the incorporation of radiolabeled hypoxanthine by the parasite and the inhibition of incorporation is attributed to the activity of anti-alaric drug candidates. For each trial, tested antimalarials such as chloroquine, mefloquine, quinine, artemisinin and pyrimet aniña are used. The incubation period is 66 hours and the initial parasitaemia is 0.2% with a hematocrit 1%. The medium is an RPMI-1640 culture with a non-folate or p-aminoben zoic acid. Albumax more than inactivated human plasma at 10% normal heating is used as, with Albumax, minor protein ligament, and compounds that produce slightly high activities in this model. If a compound is exposed with no prior knowledge of the activity, it "dissolves directly into dimethyl sulfoxide (DMSO), and is diluted 400 times with the complete culture medium." The unknown compound is initiated at a maximum concentration of 50,000 ng ml "1 and sequentially diluted 2 times by 11 times to provide a concentration range of 1048 times. These dilutions are carried out automatically by a 1000 Biomek Liquid Handling system in 96-well microtiter plates. The diluted drugs are then transported to test plates, 200 μl of parasite-infested erythrocytes are added, and incubated at 37 ° C in a controlled environment of 5% C02, 5% 02 and 90% N2. 25 μl of 3H-hypoxant ina is added after 42 hours, and the plates are incubated for a further 24 hours. The plates are frozen at -70 ° C, after 66 hours to cause lysis of the red cells, and then melted and harvested on a fiberglass filter pad in a 96-well harvester. The filters are then counted in a scintillation counter. For each drug, the concentration response profile is determined and the inhibitory concentrations of 50%, 90% and 10% (IC5o, IC90 and IC10) are determined by a logistic dose response non-line 1 response program.

A pre-selection structure can be used where a 3-dilution assay can be used to determine activity in a high medium or low concentration. The concentrations are selected as 50,000, 500 and 50 ngm "1. These are carried out in duplicate in a 96-well structure plate with 14 test compounds and an unknown compound (standard) per plate. a Biomek diluent for the mixing and dilution of medicines and the addition of medicines and parasites to a test plate In the pre-protective structure, if the FIELD OF ANALYSIS (AF) has an "< ", then the compound is" very active "and the IC values will most likely be below the last dilution value (in nanograms / ml), which are listed after AF.In many cases, these compounds are run again to a low start concentration to determine the true IC value, if the AF has a "> ", then the IC value is greater than the preprotective dilution value, thus" AF > 250"means that the IC value is greater than 250 ng ml -i and one Additional protection is not carried out. In these cases, the values of 0.00 are introduced for the IC values. The results are shown in Table IV of aba or: Table IV O 1 Table IV (cont) I It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property:

Claims (27)

1. CLAIMS A compound of general formula I or salts thereof, characterized in that Y represents a halogen atom, a cycloalkyl, or an aryl group, C-linked heteroaryl, or optionally substituted erocyclylalkyl or a -NR ^ 2 group; where R represents a hydrogen atom or an optionally substituted alkyl, alkenyl or alkynyl group; R represents an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl group; or - - R1 and R2 together with the interjacent nitrogen atom represents an optionally substituted heterocyclic group or an amino group derived from an optionally subsitric acid amino ester. 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. 2. A compound according to claim 1 characterized in that Y represents a halogen atom.
3. 3. A compound according to claim 1 or claim 2, characterized in that Y represents a fluorine or bromine atom.
4. 4. A compound according to claim 1, characterized in that Y represents a C3_8 cycloalkyl group / a C6-i8 aryl group - a 5- to 10-membered heteroaryl C-bonding group or - - a C6_6 heterocyclyl alkyl group of 5 to 10 members, each group is optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxy, C? - alkyl, C2_ alkenyl, C? _4 haloalkyl, C-alkoxy ? -, amino, alkylamino C? -, di (alkyl) amino, carboxyl, C 1 -aryl aryl / 5- to 10-membered heterocyclic groups and 5- to 10-membered heterocyclic alkyl or phenyl-substituted members.
5. 5. A compound according to claim 4, characterized in that Y represents an aryl Cß-iß group optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, C alquilo- / C al-alkenyl, haloalkyl C? _4 , C? -4 alkoxy, C? _4 haloalkoxy, amino, C alqu _ alkylamino, di (C? _) alkyl amino and carboxyl groups.
6. 6. A compound according to claim 4 or rei indication 5, characterized in that Y represents a phenyl, naphthyl, anthryl or phenanthryl group, each group is optionally - - substituted by one or more substituents selected from the group consisting of halogen atoms, and hydroxyl, methyl, vinyl, C4-4 alkoxy and carboxyl groups.
7. 7. A compound according to any one of claims 4 to 6, characterized in that Y represents a phenyl, f luoro-phenyl or chlorophenyl, bromophenyl, t-rimet i-1-phenyl, vinylphenyl, phenyl-phenyl, dimethyl-phenyl, t rime toxiphenyl, carboxy lf enyl, naphthyl, hydroxynaphthyl, me phyta toxin, anthryl or phenanthryl.
8. 8. A compound according to any one of claims 4 to 1 characterized in that Y represents a phenyl or trimethoxy phenyl group.
9. 9. A compound according to claim 1 characterized in that Y represents a group -NRXR2 where R1 represents a hydrogen atom or a C4 _4 alkyl group and R2 represents a - - C? _6 alkyl, C 3-8 cycloalkyl, Cß-io aryl or C 7 - aralkyl group, or R 1 and R 2 together with the interjacent nitrogen atom represents a 5- to 10-membered heterocyclic group or an amino group derived from an ester C6 alkyl of an amino acid, each group is optionally substituted by one or more substituents selected from the group consisting of halogen atoms, C? - alkyl, C? _4 haloalkyl, C? _6 alkoxycarbonyl, phenyl, halophenyl, alkylphenyl groups C? -4, haloal qui 1 pheny1 or C? -, alkoxyphenyl C? _4, benzyl, pyridyl, and pyrimidinyl.
10. 10_. A compound according to claim 9, characterized in that Y represents a group -NRXR2 wherein R1 represents a hydrogen atom or a C4_4 alkyl group, and R2 represents a C ?_ alkyl, C3_6 cycloalkyl / phenyl or benzyl group, or R1 and R2 together with the interjacent nitrogen atom represent a 6 to 10 membered heterocyclic group or an amino group derived from an amino acid C C4 alkyl ester, each group is optionally substituted by one or more - - substudents selected from the group consisting of halogen atoms, haloalkyl groups C4-4, alkoxycarbonyl C1-4, phenyl, halophenyl, alkylphenylC4-4, haloalkyl 1 phenyl C4-4, alkoxyphenyl C6, benzyl, pyridyl and pyrimidinyl .
11. 11. A compound according to claim 9 or claim 10 characterized in that Y represents a propylamino group, cyclopentel 1 amino, cyclohexylamino, phenylamino, fluoropheniumlamino, chloro phenyl amino, bromo phenylamino, iodine phenylamino, methoxycarbonyl phenylamino, biphenylamino, benzylamino, fluorobenzylamino, bis (tri fluoromethyl) benzylamino, phenylethylamino, phenyl-methoxycarbonylmethylamino, diethylamino, morpholinyl, thiomorpholinyl, morpholines ol fi oni 1, indolinyl, tetrahydroisoquinolinyl, phenylpiperazinyl, fluorophenylpiperazinyl, chlorophenylpiperazine, methylphenylpiperazine In? lo, trifluororne-tylphenylpiperazinyl, methoxy phenylpiperazinyl, benzylpiperazinyl, pyridylpiperazinyl and pyrimidinylpiperiinyl. - -
12. 12. A compound according to any one of the rei indications 9 to 11 / characterized in that Y represents a propylamino, phenylamino, bromopheni 1 amino, iodophenylamino, bi phenylamino, benzylamino, bis (trifluoromet i 1) benzylamino, phenylethylamino, phenyl group -me t oxycarbonylme lamino or morpholinyl.
13. 13. A compound according to any one of the preceding claims, characterized in that the parasite is an organism of the genus Neospora or the genus Eimeria.
14. 14. The use of a compound of the general formula I according to any of claims 1 to 12, for the manufacture of a medicament for the treatment and / or prophylaxis of a disease caused by infection with a different parasite after an organism of the genus Plasmodium. - -
15. 15. The use according to claim 14 characterized in that the parasite is an organism of the genus Neospora or the genus Eimeria.
16. 16. A compound of the general formula I according to any one of claims 1 to 12, characterized in that it has the condition that, when Y is a group -NR1R2 and R2 represents a phenyl group, 3-chloropheni-1 or, 4-chlorophenyl , 3-bromofenyl, -bromo phenyl, 4-iodophenyl, 4-methyphenylphenyl, 4-methoxyphenyl, 3-carboxyphenyl, or 4-cerboxi phenyl, and R 1 is an optionally substituted alkyl group.
17. 17. A process for the preparation of a compound of the general formula I according to claim 16, characterized in that it comprises reacting a compound of the general formula II - - wherein Q represents a hydrogen atom or a t-dimethyl silyl group, with a suitable halogenating agent to form a compound of the general formula I wherein Y represents a halogen atom; and if desired, reacting the compound of the general formula I so as to form one or the other with a Gringnard reagent of the general formula? MgX wherein Y is an optionally substituted cycloalkyl group, aryl, C-heteroaryl or heterocyclyl ether; and X is a halogen atom to form a compound of the general formula I wherein Y represents a cycloalkyl, aryl heteroaryl-C or heterocyclic heteroaryl, or optionally substituted with an amine of the general formula HNR1R2 wherein R1 and R2 are as defined in claim 13 to form a compound of the general formula I in where Y represents a group -NR ^ 2 where R1 and R2 are as defined above.
18. 18. A process in accordance with the rei indication 17, characterized in that a compound of the general formula I in which Y represents a bromine atom generated by the reaction of a compound of the general formula II wherein Q represents a tr ime t ils group il il or with bromot rimet ilsilano.
19. 19. A process for the preparation of a compound of the general formula I according to claim 16, characterized in that Y represents a cycloalkyl, aryl, C-heteroaryl or heterocyclic group optionally substituted which comprises reacting 9, 10 -anhydroart emisinin with a compound of the general formula YH, where Y is as defined above, in the presence of an appropriate Lewis acid.
20. 20. A process for the preparation of a compound of the general formula I as defined in claim 1 characterized in that Y represents an optionally substituted C-aryl or heteroaryl group which optionally comprises reacting 10-t-ricloroacet imidoi-10-deoxoartemis inine with a compound of general formula YH, where Y is as defined previously, in the presence of an adequate Lewis acid.
21. 21. A process according to claim 18, characterized in that the 10-trichloroacetimidoyl-10-deoxoartemis inine is generated in situ by reacting a compound of the formula II as defined in claim 17 wherein Q represents a hydrogen atom with trichloroacetonitrile in the presence of an adequate base.
22. 22. A process for the preparation of a compound of the general formula I as defined in claim 1 characterized in that Y represents an aryl, or heteroaryl, group C optionally substituted which comprises making reacting a compound 10-a loxiartemi sina inina where the acyloxy group is of the formula A- (C = 0) -0-, where A represents an optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclic or polycyclic group, with a composed of the general formula YH, where Y is as defined above, in the presence of a Lewis acid.
23. 23. A pharmaceutical composition characterized in that it comprises a carrier and, as an active ingredient, a compound of the general formula I according to claim 16.
24. 24. A compound of the general formula I according to claim 16 for use in the treatment and / or prophylaxis of the disease caused by infection with a parasite of the genus Plasmodium.
25. 25. The use of the compound of the general formula I according to claim 16 for the manufacture of a medicament for the treatment and / or prophylaxis of a disease caused by infection with a parasite of the genus Pia smodium.
26. 26. A method for the treatment of a disease caused by infection with a parasite different from an organism of the Plasmodium genus characterized in that it comprises administering to a horse in need of said treatment a therapeutically effective amount of a compound of the general formula I as defined in the rei indication 1.
27. 27. A method for the treatment of a disease caused by infection with a parasite of the genus Plasmodium, characterized in that it comprises the administration to a horse in need of said treatment of a therapeutically effective amount of a compound of the general formula I in accordance with the claim 16