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WO2000004025A1 - Derives d'artemisinine antiparasitaires (endoperoxydes) - Google Patents

Derives d'artemisinine antiparasitaires (endoperoxydes) Download PDF

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Publication number
WO2000004025A1
WO2000004025A1 PCT/GB1999/002272 GB9902272W WO0004025A1 WO 2000004025 A1 WO2000004025 A1 WO 2000004025A1 GB 9902272 W GB9902272 W GB 9902272W WO 0004025 A1 WO0004025 A1 WO 0004025A1
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group
compound
alkyl
optionally substituted
formula
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PCT/GB1999/002272
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English (en)
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Richard Kingston Haynes
Ho-Wai Chan
Wai-Lun Lam
Hing-Wo Tsang
Gisela Greif
Gabriele Schmuck
Arnd Voerste
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The Hong Kong University Of Science & Technology
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Priority to AU49222/99A priority Critical patent/AU4922299A/en
Publication of WO2000004025A1 publication Critical patent/WO2000004025A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/18—Bridged systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • 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.
  • Neospora spp . including Neospora caninum
  • the final host for Neospora spp . 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.
  • 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.
  • Coccidiosis an infection of the small intestine, is relatively rarely diagnosed in humans, where it is caused by Isospora belli.
  • humans are also the final host of at least two cyst -forming coccidial species (Sarcocystis suihominis and S. bovihomlnis) .
  • Coccidia phylum Apicomplexa, suborder Eimeriina
  • 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) .
  • 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.
  • drug- resistant strains of Eimeria have emerged and drug- resistance is now a serious problem. New drugs are therefore urgently required.
  • 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 .
  • the oxygen atom at C-10 can be either removed to provide 10-deoxyd ⁇ hydroartem ⁇ smm, 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
  • 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.
  • 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 ⁇ m ⁇ dazol-1-yl group and demonstrated that these compounds are active against Plasmodium falciparum.
  • 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.
  • W represents a hydrogen atom or an oxo group
  • X represents a group -S(0) n R where n is 0, 1 or 2 , -NR X R 2 , -CHR 3 R 4 or Ar;
  • R represents an optionally substituted alkyl, aryl , heterocyclic or polycyclic group
  • R 1 and R 2 independently represent an optionally substituted alkyl, cycloalkyl, aryl or aralkyl group
  • R 1 and R 2 together with the interjacent nitrogen atom represent an optionally substituted heterocyclic group or an amino group derived from an optionally substituted amino acid ester;
  • R 3 represents a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl, aryl or alkoxycarbonyl group
  • R 4 represents a nitro group or an optionally substituted alkyl, alkenyl, alkynyl, aryl, alkanoyl , aroyl , alkoxycarbonyl or aryloxycarbonyl group
  • R 3 and R 4 together with the interjacent carbon atom represent an optionally substituted cycloalkyl or polycyclic group
  • 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 ⁇ -R 2 where R 1 and R 2 are as defined above are particularly suitable for the formation of such acid addition salts.
  • Any alkyl, alkenyl or alkynyl group 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ -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.
  • 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.
  • 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.
  • 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 .
  • X represents a group -S(0) n R and R represents a alkyl, C 6 _ 18 aryl, 3- to 14- membered heterocyclic or C 4 _ 14 bicyclic group, each group being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxyl, C ⁇ alkyl, C 1 _ i haloalkyl, C x _ 4 alkoxy, alkoxycarbonyl groups.
  • X represents represents a group -S(0) n R and R represents a Cj . alkyl, C 6 .
  • 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) n R, n is 0.
  • X may represent a group -NR 1 R 2 where R 1 and R 2 independently represent a C LS alkyl, C 6 _ 10 aryl or C 7 _ 16 aralkyl group, or R 1 and R 2 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.
  • X represents a group - R ⁇ 2 where R 1 and R 2 independently represent a C x.4 alkyl or C 7-10 aralkyl group, or R 1 and R 2 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 .
  • X represents a diethylamino, dibenzylamino, morpholinyl or indolinyl group.
  • X represents a dibenzylamino or indolinyl group
  • X may represent a group -CHR 3 R 4 where R 3 represents a hydrogen atom or a C , : alkyl or C,tician alkoxycarbonyl group and R'" represents a nitro, C ⁇ alkyl, C ⁇ alkanoyl, C 7 _ X1 aroyl , C x _ 6 alkoxycarbonyl or C 6 _ 10 aryloxycarbonyl group, or R 3 and R 4 together with the interjacent carbon atom represent a C 3 ⁇ 8 cycloalkyl or C 4 _ 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, C 1 _ i haloalkyl, C 1-4 alkoxy and C ⁇ haloalkoxy groups.
  • X may represent a group represents a group -CHR 3 R 4 where R 3 represents a hydrogen atom or a C 1-4 alkyl or C ⁇ alkoxycarbonyl group and R 4 represents a nitro, C 1-4 alkyl, C 1 _ 4 alkanoyl, benzoyl , C x _ 4 alkoxycarbonyl or benzoxycarbonyl group, or R 3 and R 4 together with the interjacent carbon atom represent a C 3 _ 6 cycloalkyl, C 6 _ 10 bicyclic or C 6 _ 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 C 1 . 4 haloalkyl groups.
  • 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.
  • X represents a C 6 _ 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, C 7 _ 10 aralkyl and heterocyclic groups.
  • X represents a C 6 _ 10 aryl group optionally substituted by one or more substituents selected from the group consisting of halogen atoms, C, 4 alkyl, C, dilemma alkoxy, di ⁇ C 1 4 alkyl) amino and heterocyclic groups.
  • X represents a phenyl, chlorophenyl or bromophenyl group .
  • 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.
  • the parasite is an organism of the genus Neospora or the genus Eimeria .
  • 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 -CHR 3 R 4 where R 3 represents a hydrogen atom, then R 4 does not represent an ethyl, n-propyl or 4-chlorobenzyl group.
  • 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
  • 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
  • Nu is a nucleophilic group of formula -SR, -NR X R 2 , -CHR 3' R 4' or Ar where R, R 1 , R 2 and Ar are as defined above, R 3' 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 ⁇ 2 , -CHR 3' R 4' or Ar where R, R 1 , R 2 , R 3' , R 4' and Ar are as defined above; if desired, reacting a compound of the general formula QNu where Q is
  • 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.
  • 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.
  • 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 -S0 2 R, 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 -S0 2 R 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 .
  • the metallated secondary amme may be conveniently prepared by reacting a secondary amme of formula HNR X R 2 , where R 1 and R 2 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.
  • 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.
  • the lithiated acetyl reagent may be conveniently prepared by reacting an acetyl compound of formula
  • lithiating agents for this reaction include lithium diisopropylamide or a similar lithium dialkylamide base or lithium hexamethyldisilazide .
  • 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
  • a suitable solvent particularly an ether solvent such as tetrahydrofuran or diethyl ether
  • W represents an oxo group
  • X represents a group -CHR 3' R 4'
  • R 3' and R 4' are 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.
  • 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 -CHR 3 'R 4' as defined above may be conveniently prepared by reacting, for instance, sodium hydride with a compound of formula CH 2 R 3' R 4 ' , where R 3' and R 4' are as defined above.
  • 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.
  • 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.
  • the reaction is carried out at a temperature at or below 0°C, preferably about -10°C.
  • 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.
  • 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, R 1 , R 2 , 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.
  • 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.
  • the reagents are initially mixed together at 0°C and the reaction mixture is then subsequently heated at reflux temperature .
  • -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 R 4 " is a group -CH 2 R 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
  • the reaction is carried out at room temperature, that is, 15 to 35°C, preferably 20 to 30°C.
  • 10-Hydroperoxy-lO-d ⁇ hydroartem ⁇ s ⁇ tene (9-hydro- peroxyartemisitene) may be prepared by reacting 9,10- anhydrodehydroartemis m of formula
  • 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-hydroperoxyartem ⁇ s ⁇ tene is therefore singlet oxygen.
  • 10-Anhydrodehydroartem ⁇ smm may be prepared by reacting dihydroartemismm with a dehydrating agent, such as boron t ⁇ fluoride 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.
  • a dehydrating agent such as boron t ⁇ fluoride dietherate
  • 10-Anhydroartem ⁇ smm may also be conveniently prepared by reacting dihydroartemismm with t ⁇ fluoroacetic 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.
  • the reaction is carried out m the presence of a base, such as py ⁇ dme or a derivative thereof, for example, dimethylammo- pyridine
  • a base such as py ⁇ dme or a derivative thereof, for example, dimethylammo- pyridine
  • 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 HNR 1 R 2 , acetyl compounds of formula - CH 2 R 3' R 4' and aryl halide compounds of formula ArHal where R, R 1 , R 2 , 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.
  • R 4 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 ZCHR 3 R 4 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.
  • AIBN also known as 2 , 2 ' -azobis [2-methylpropane-nitrile]
  • AIBN converts tri-n-butyltin hydride into the tributyltin radical which abstracts halogen from the compound of formula ZCHR 3 R 4 to provide a carbon radical which adds to the exocyclic double bond of artemisitene.
  • 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 -CHR 3 R 4 , where R 3 and R 4 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.
  • 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.
  • 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 ZCHR 3 R 4 are known compounds or can be prepared by processes analogous to known processes.
  • compositions 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.
  • 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.
  • solid carriers such as, for example, lactose, starch or talcum
  • 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-isole
  • 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 .
  • 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.
  • 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.
  • 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 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, ⁇ m ⁇ dazol-1-yl , n-pentyl, n-t ⁇ decyl 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
  • the parasiticidal activity of compounds of the invention was investigated by means of the following test .
  • RPMI growth medium for cell cultures
  • the assay relies on incorporation of radiolabelled hypoxanthine by the parasite and inhibition of incorporation is attributed to activity of known or candidate antimala ⁇ al drugs.
  • 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.
  • 3 H-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 (IC 50 , IC 90 and IC 10 ) 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.
  • the ANALYSIS FIELD 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 .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

La présente invention se rapporte à l'utilisation de certains dérivés substitués en C9 de l'artémisinine de la formule générale (I), ou d'un sel de ceux-ci dans le traitement curatif et/ou préventif de maladies dues à l'infection par un parasite, à de nouveaux dérivés substitués en C9 de l'artémisinine, à leurs procédés de préparation et à des compositions pharmaceutiques contenant ces dérivés substitués en C9. Les composés de l'invention s'avèrent particulièrement efficaces dans le traitement de la malaria, de l'infection à Néospora et de la coccidiose.
PCT/GB1999/002272 1998-07-14 1999-07-14 Derives d'artemisinine antiparasitaires (endoperoxydes) WO2000004025A1 (fr)

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EP98305628 1998-07-14
EP98305628.4 1998-07-14
EP98307664.7 1998-09-22
EP98307664 1998-09-22

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WO2001064682A1 (fr) * 2000-03-03 2001-09-07 Japan Science And Technology Corporation Nouveau compose dote d'une activite antipaludique
WO2007049820A1 (fr) 2005-10-28 2007-05-03 Takeda Pharmaceutical Company Limited Compose amide heterocyclique et utilisation de celui-ci
US8815942B2 (en) 2010-10-20 2014-08-26 The Royal Institution For The Advancement Of Learning/Mcgill University Combination therapy and uses thereof for treatment and prevention of parasitic infection and disease
EP3539549A1 (fr) 2018-03-12 2019-09-18 Adisseo France S.A.S. Additif alimentaire à base de saponines pour le traitement de la coccidiose
CN114276365A (zh) * 2021-12-30 2022-04-05 张家港威胜生物医药有限公司 一种蒿甲醚杂质脱水双氢青蒿素的制备方法

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001064682A1 (fr) * 2000-03-03 2001-09-07 Japan Science And Technology Corporation Nouveau compose dote d'une activite antipaludique
US6710074B2 (en) 2000-03-03 2004-03-23 Japan Science And Technology Corporation Compound having antimalarial activity
WO2007049820A1 (fr) 2005-10-28 2007-05-03 Takeda Pharmaceutical Company Limited Compose amide heterocyclique et utilisation de celui-ci
US8815942B2 (en) 2010-10-20 2014-08-26 The Royal Institution For The Advancement Of Learning/Mcgill University Combination therapy and uses thereof for treatment and prevention of parasitic infection and disease
US9278086B2 (en) 2010-10-20 2016-03-08 The Royal Institution For The Advancement Of Learning/Mcgill University Combination therapy and uses thereof for treatment and prevention of parasitic infection and disease
EP3539549A1 (fr) 2018-03-12 2019-09-18 Adisseo France S.A.S. Additif alimentaire à base de saponines pour le traitement de la coccidiose
CN114276365A (zh) * 2021-12-30 2022-04-05 张家港威胜生物医药有限公司 一种蒿甲醚杂质脱水双氢青蒿素的制备方法

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