Title of Invention

"DUAL MOLECULES CONTAINING A PEROXIDE DERIVATIVE, SYNTHESIS AND THERAPEUTIC APPLICATIONS THEREOF"

Abstract

Dual molecules characterized in that they consist of coupling products having the formula (I) wherein -A represents a residue of molecule with anti-malarial activity, -Y1 and Y2, identical or different, represent a linear or ramified alkylene chain at CI to C5, containing if applicable one or more amine, amide, sulphonamide, carboxyl, hydroxyl, ether or thioether radicals, said alkylene chain at C1 to C5 being substituted if applicable by an alkyl radical at C1 to C5, with the possibility of either Y1 or Y2 being absent, -U is an amine, amide, sulphonamide, carboxyl, ether or thioether function, said function linking Y1 and Y2, -Z1 and Z2, identical or different, represent a saturate or unsaturated, linear, ramified or cyclic arylene or alkylene radical, with the possibility of either Zi or Z2 being absent, or Z1 + Z2 together represent a polycyclic structure including the junction carbons Ci and Cj, -R1 and R2, identical or different, represent a hydrogen atom or a functional group capable of increasing the hydro solubility of the dual molecule, advantageously selected from -COOH, -OH, -N(Ra, Rb) where Ra and Rb, identical or different, represent a hydrogen atom or an alkyl radical at C1 to C5. -Rx and Ry, form a cyclic peroxide with 4 to 8 chain links, which may comprise 1 or 2 additional oxygen atoms in the cyclic structure, Cj being one of the peaks of said cyclic peroxide, or -Rx and Ry, is a cyclic peroxide with 4 to 8 chain links, which may comprise 1 or 2 additional oxygen atoms in the cyclic structure, and one or more substituents R3, identical or different, occupying any separate positions on the cycle, at least one representing a halogen atom, an -OH group, a -CF3 group, an aryl radical, an alkyl or alkoxy radical at CI to C5, an -NO2 group, the other substituent (s) having one of these correspondences or a hydrogen atom, with the possibility of substituting the carbonated peaks of the cyclic peroxide if applicable by one or more substituents as claimed for R3, with the possibility of two adjacent substituents forming a cyclic structure with 5 to 6 chain links, saturated or unsaturated, if applicable substituted by one or more substituents R3 in any position, with the possibility of the other substituent Rx or Ry being R3, and their addition salts with pharmacological acceptable acids.

Full Text

FORM 2 THE PATENTS ACT 1970 [39 OF 1970] & The Patents Rule, 2003 COMPLETE SPECIFICATION [See Section 10 and Rule 13] 'DUAL MOLECULES CONTAINING A PEROXIDE DERIVATIVE, SYNTHESIS AND THERAPEUTIC APPLICATIONS THEREOF" CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE [C.N.R.S.], of 3, rue Michel-Ange, F-75794 Paris, France, The following specification particularly describes the nature of the invention and the manner in which it is to be performed:- The invention relates to dual molecules containing a peroxide derivative, showing particularly an anti-malarial activity, the synthesis and therapeutic applications of said molecules. Malaria is one of the primary infectious causes of mortalitv in the world and affects 100 to 2Q0 million people, a year. The signiffiant'upsurge in the disease-observed in recent years is due to several factors, including: the carriers, i.e. Anopheles, which are becoming resistant to conventional inexpensive insecticides such as DDT (abbreviation of trichloro-1,1,1-di(p-chloro-phenyl)-2,2 ethane); - population growth in at-risk zones and, • essentially, -the resistance'of numerous strains of Plasmodium' falciparum, ' the parasite responsible' for the mortal forms of the disease, to the medicinal products :onventiorially used, such as chloroquine and mefloquine. The discovery of artemisinine 1, 2, a powerful anti-malarial agent extracted from Artemisia annua, drew attention, to molecules comprising, like artemisinine, an endoperoxide function 3, 4. Artemisinine and some of its hemi-synthetic derivatives, such as artemether and artesunate, have iproved to be very active on resistant P. falciparum Istrains. However, the high cost of these natural compounds and uncertain supply represent major disadvantages. Therefore, the interest of synthetic anti-malarial compounds, which would be accessible at low prices, and offer an action mechanism similar to that of artemisinine, an alkylating effect on the blood and/or parasitic proteins, will be evaluated. Research on such compounds by the inventors led to the development of a new synthesis strategy based on the use of- . compounds liable both to be accumulated effectively in the parasite and exert an effect such as that of artemisine. The inventors observed that forming a covalent bond between a compound with anti-malarial properties and a peroxide type derivative offered coupling products with, surprisingly, a synergic effect between the penetration capacity and activity of the respective constituents on chloroquine-resistant strains and as a general rule a high efficacy for a wide range of parasites. Therefore, the invention relates to dual molecules Dresented in the form of coupling products, showing particularly an anti-malarial activity, in particular m P. falciparum. It also relates to a synthesis method for such molecules, comprising a limited number of steps, involving low-cost products, and therefore easy to implement at an industrial scale. The invention also relates to biological applications of said molecules and particularly the use of their anti-malarial properties to develop medicinal products. The dual molecules according to the invention are characterised in that they consist of coupling products complying with the formula I wherein -A represents a residue of molecule with anti¬malarial activity, Y1 and Y2, identical or different, represent a linear or ramified alkylene chain ' at CI to C5, containing if applicable one or more amine, amide, sulphonamide, carboxyl, hydroxyl, ether or thioether radicals, said alkylene chain at CI to C5 being substituted if applicable by an alkyl radical at CI to C5, with the possibility of either Y1 or Y2 being absent, -U is an amine, amide, sulphonamide, carboxyl, ether or thioether function, said function linking Yi' and Y2, -Zx and Z2, identical or different, represent a saturated or unsaturated, linear, ramified or cyclic arylene or alkylene radical, with the possibility of either Zx or Z2 being absent, or Zi + Z2 together represent a polycyclic structure including the junction carbons Ci and Cj, -R1. and R2, identical or different, represent a hydrogen atom or a functional group capable of increasing the hydrosolubility of the dual molecule, advantageously selected from -COOH, -OH, -N(Ra, Rb) where Ra and Rb, identical or different, represent a hydrogen atom or an alkyl radical at CI to C5, -Rx and Ry form a cyclic peroxide with 4 to 8 chain links, Cj being one of the peaks of said cyclic peroxide, or -Rx or Ry is a cyclic peroxide with 4 to 8 chain links, which , may comprise 1 or 2 additional oxygen atoms in the cyclic structure, and one or more substituents R3/ identical or different, occupying any separate positions on the cycle, at least one representing a halogen atom, an -OH group, a -CF3 group, an aryl radical, an alkyl or alkoxy radical at CI to C5, an -N02 group, the other substituent (s) having one of these correspondences or a hydrogen atom, with the possibility of substituting the carbonated peaks of the cyclic peroxide if applicable by one or more substituents as defined for R3, with the possibility of two adjacent substituents forming a cyclic structure with 5 to 6 chain links, saturated or unsaturated, if applicable substituted by one or more substituents R3 in any position, with the possibility of the other substituent Rx or Ry being R3, and their addition salts with pharmacological acceptable acids. Advantageously, the residue A drains the coupled compound inside the parasite, which then has an alkylating effect on the blood and/or parasitic proteins. In a preferred family of derivatives according to the invention, A represents a nitrous heterocycle selected from an aminoquinoline according to formula II or a 1,5-naphtyridine according to formula III below wherein -R3 represents one or more identical or different substituents occupying separate position, at least one representing a halogen atom, an -OH group, a -CF3 group, an aryl radical, an alkyl.or alkoxy radical at CI to C5, an- -N02 group, the other substituent (s) having one of these correspondences or a hydrogen atom, -R4 represents a linear, ramified or cyclic alkyl radical at CI to C5, or a hydrogen atom. In another preferred family according to the invention, A represents a radical according to formula IV R5 CHOH ■ (IV) wherein R5 represents an aryl radical or a nitrous heterocyclic residue. Preferred correspondences for R5 consist of 9-phenanthrenyl or 4-quinolinyl radicals, possibly substituted by one or more R3 groups. In another preferred family, A represents a phenol-2(aminomethyl) residue according to formula V wherein R3, Ra and Rb are as defined above. or cycloguanil according to formula VII Another preferred family. of ' dual molecules according to the invention comprises a substituent A representing a biguanide residue selected from proguanil derivatives according to formula VI (VII) wherein R,3 is as defined above. In another preferred family, A represents a esidue of pyrimidine and more particularly of yrimethamine according to formula VIII or formula IX wherein R3 is as defined above. In another preferred family according to the invention, A represents an acridine residue according to formula X (X) wherein R3 and R4 are as defined above. The invention relates to dual molecules, such as those defined above, in particular corresponding'to the preferred families mentioned above, and wherein Rx and RY form a cyclic peroxide together. In more specially preferred dual molecules of this type, Rx and Ry represent a trioxane substituted by one or more substituents R3. In another preferred embodiment of the invention, used advantageously with the previous embodiment, Z\ and Z2 represent a cyclohexyl or bi-cyclopentyl radical. In another preferred embodiment, used if required with at least one of the previous embodiments, Yx - U -Y2 are selected so as to modulate the hydrosolubility of the molecule to give it optimal activity. The invention also relates to a synthesis method for the molecules defined above. This method comprises the reaction of reactive derivatives of A and peroxide derivatives comprising the residues Rx' and Ry, so as to form, between these derivatives, a link as defined in relation to formula I. (XI) Various synthesis processes will be easy to access for those skilled in the art using conventional techniques. For example, for peroxide synthesis, it is possible to refer to the work by S. Patai, "The Chemistry of peroxides", John Wiley and Sons Ltd, 1983. In this way, to prepare dual molecules comprising a trioxane as the peroxide and an aminoquinoline as the derivative A, a compound according to formula XI wherein K3 -is as defined above and "hal" represents a halogen atom, is reacted with a diamine derivative according to formula XII ' R4—NH— Yr-u, (XII) where R4 and Yx are as defined above and U^. represents an -NH2 group, producing a compound according to formula XIII wherein R3, R4 and Yx are, as defined above, b)-irradiation in the presence of molecular oxygen and a photosensitising agent, of a derivative according to formulas XIV to XVII below followed by the reaction with a diketone, such as 1,4-cyclohexadione according to formula XVIII or cis-bicyclo(3.3.0]octane-3,7-dione according to formula XIX producing trioxanes functionalised with a ketone, according to the general formula XX, (XX) o—o' wherein Zx, Z2 and R3 are as defined above, c)-coupling of the derivative according to formula XIII with the trioxane according to formula XX, by reductive amination, followed if applicable by a reaction with a pha.rmaceutically acceptable acid, to obtain the coupling product in salt form. Step a is advantageously carried out at a. temperature of 80°C to 140°C with stirring. The diamine derivative is preferentially used at a rate of 5 molar equivalents. After cooling, the product obtained is recovered by extraction, for example using an organic solvent such as dichloromethane, and then treated if required, for purification purposes. To carry out step b, photosensitised oxygenation of the initial olefin is performed in the presence of molecular oxygen. The photosensitising agent is advantageously a conventional agent such as tetra-phenylporphyrine or Bengal pink. The peroxide obtained is then reacted with a diketone, preferentially at a rate of 4 to 10 molar equivalents. The reaction is advantageously carried out in the presence of trimethyl silyl trifluorpmethane sulphonate, at a temperature below -50°C, particularly -70°C, for several hours. The functionalised trioxane is then purified. Column chromatography is used for example. A similar protocol is used for the synthesis of trioxane as the precursor of trioxaquines according to formula XIII: 2,3-dimethylbut-2-ene is photo- oxygenated under the above conditions and then placed in the presence of 2 to 10 molar equivalents of an oxoaldehyde, a few drops of trifluoroacetic acid and 2 molar equivalents of N-iodosuccinimide. The reaction is carried out at ambient temperature and protected from light for several ho:urs. The functionalised trioxane is then purified using column chromatography for example. The coupling step c between the ketone and primary amine is carried out in the presence of a reductive agent such as sodium triacetoborohydride,. at ambient temperature. These compounds are used according to a primary amine/ketone molar ratio of approximately 1.25, the reductive agent being used at a rate of 1.25 equivalents/ketone. To obtain the coupling product in salt form, the basic nitrogens undergo protonation, by adding a pharmacological acceptable acid. For example, citric, tartaric, oxalic and fumaric acid may be used. The reaction may be carried out with 2 acid equivalents. The protonated product is then recovered and subjected to one or more purification steps if required. The study of the pharmacological properties of the coupling products according to the invention demonstrated an anti-malarial effect on P. falciparum cultured in human red blood cells. It' is particularly important to obtain such an effect as the resistance phenomena of Plasmodium falciparum strains, the mortal species, are developing with respect to standard anti-malarial drugs and, in addition, vaccination protection, the subject of considerable research, will not be available for several years. Therefore, the invention relates to the use of the properties of these "coupling products, which also offer the advantage of high safety, to produce pharmaceutical formulations. The pharmaceutical formulations according to the invention are characterised in that they comprise an effective quantity of at least one coupling product as defined above, associated with a pharmaceutically inert vehicle. These formulations comprise if required active ingredients of other medicinal products. This may involve an association with any other anti-malarial molecule (amino-quinoline, aryl-alcohol comprising an amine function, amino derivatives of orthocresol, sulphones, sulphonamides, biguanides, amino-pyriminidines, amino-triazines, or quinazolines, and antibiotics (tetracycline, rifampicine, gramicindine D, valinomycine and quinolones in particular) and anti¬fungal agents with an anti-malarial activity). They will also be used advantageously with compounds promoting their assimilation such as sugars like glucose. The formulations according to the invention are particularly suitable for the treatment of malaria.. Therefore, the invent ion. also relates to the application of the coupling products defined above to the development of medicinal products to treat malaria. The sales packaging materials, particularly the labelling and package inserts, and advantageously the packaging, are produced according to the planned specific therapeutic application. The pharmaceutical formulations according to the invention may be administered in different forms, more specifically by the oral, rectal or injectable route. Formulations administered orally advantageously comprise 40 to 300 mg of active ingredient per dosage unit, preferentially 40 to 100 mg. They advantageously come in the form of tablets, pills, capsules or drops in particular. The injectable forms comprise 2 0 to 3 00 mg of active ingredient per dosage unit, preferentially 50 to 100 mg. They come in the form of solutions for injection by the intravenous, subcutaneous or intramuscular route, produced from sterile or sterilisable solutions. Suspensions or emulsions may also be used. For rectal administration, suppositories are used. For example, the dosage that may be used in humans corresponds to the following doses: the patient is administered 50 to 300 mg/day for example, in one or more doses for malaria treatment. The invention also relates to biological reagents, wherein the active ingredients are composed of .the derivatives defined above. These reagents may be used as references or standards in studies on potential anti-malarial activities. The invention's other characteristics and advantages will be seen more clearly in the following examples related to the production of quinoline and trioxane coupling products, referred to as "trioxaquines", and the study of their anti-parasitic activity. The formulas of compounds 1 to 34, the synthesis of which is described in these examples are given at the end of the disclosure. Example 1: trioxaquine 4 Synthesis of 7-chloro-4-[N-(2-aminoethyl)amino]- quinoline 1 A mixture of 4,7-dichloroquinoline (2.0 g, 10 mmol) and 1,2-diaminoethane (2.7 g, 45 mmol) is heated at 85 °C for 5 hours with magnetic stirring. After adding IN soda (15 ml), the solid obtained is extracted with ethyl acetate (100 ml) at 50°C. The organic phase is washed with distilled water and then using a. saturated NaCl solution and then again with distilled water and finally is dried on sodium sulphate. The solvent is evaporated and the product obtained is vacuum-dried (1.3 g, 58%). NMR XH (250 MHz, CDCl3) 5, ppm: 8.52 (d, 3JHH =5.5 Hz, 1H, H2'), 7.94 (d, 4Jm = 2.2 Hz, 1H, H8 ' ) , 7.72 (d, 3JHH = 8.9 Hz, 1H, H5'), 7.35 (dd, 3J"HH = 8.9 Hz, 4Jm = 2.2 Hz, 1H, H6'), 6.40 (d, 3J"HH -.5.5 Hz, 1H, H3 ' ) , 5.76 (s large, 1H, HN9';), 3.32 (m, 2H, H2C10 ' ) , 3.11 (tr, 2H, H2C11'), 1.39 (s large, H2N12 ') . MS (DCI/NH3 + ) m/z (%) : 221 (2), 222 (MH+, 100), 223 (14), 224 (33), 225 (4). Synthesis of trioxane functionalised. with a ketone^ 2 A mixture of 1,4-diphenyl-l,3-cyclopentadiene (50 mg, 0.23 mmol) and tetraphenylporphyrine (5 .mg) in dichloromethane (5 ml) is irradiated in the presence of molecular oxygen (1.15 bar) for 1 hour, at 5°C, with a white bulb (200 W) . The peroxide is obtained with a quantitative yield. The unprocessed . peroxide in solution in dichloromethane is placed in a bath at -70°C; 10 molar equivalents of 1,4-cyclohexadione (260 mg, 2.3 mmol) and 0.5 equivalent of trimethylsilyl trif luoromethane sulphonate (20 fil, 0.11 mmol) are added and the reaction mixture is kept under stirring at -70°C for 4 hours. The reaction is stopped by adding triethylamine (40 /xl) . After returning to ambient temperature, the reaction medium is washed with distilled water, dried on magnesium sulphate . and evaporated to, dryness. The functionalised trioxane 2 is purified by chromatography on silica column (hexane/ethyl acetate eluent, 80/20, v/v) (yield: 55%). NMR XH (250 MHz; CDCl3) 5, ppm: 7.60-7.30 (m, 10H, H-phenyl) , 6.3 5 (d, JHH = 1-6 and 4.0 Hz, 1H, H6)', 5.2 6 (s large, 1H, H5) , 3;.31 and 3.05 (2 x d, 2Jm = 17.0 Hz, 2 x 1H, H2C6) , 2.56-2.43 (m, 5H) , 2.26 (m, 1H) , 2.05 (m, 2H). MS (DCI/NH3 + ) m/z (%)■ : 363 (MH+, 24), 364 (7), 380. (MNH4+, 100) , 381 (27) , 382 (7) . Coupling of primary amine with the ketone by reductive amination: production of trioxaquine 3 The ketone 2 (99 mg, 0.2 7 mmol) and the primary amine 1 (76 mg, 0.34 mmol) are placed in solution in CH2C12 (5 ml) . Sodium triacetoxyborohydride (72 mg, 0.34 mmol) is added. The mixture is kept under stirring at ambient temperature for 18 hours. The reaction medium is then washed with distilled water; the organic phase is dried and the solvent is evaporated to dryness (yield: 87%). NMR 2H (250 MHz, CDCl3) 5, ppm: 8.50 (2 x d, 1H, H2 ' ) , 7.95 (2 x d, 1H, H8 ' ) , 7.70 (2 x d, 1H, H5 " ) , 7.63-7.25 (m, 11H, H6' and 1 OH phenyl) , 6.35 (m, 2H, H3 ' and H6) , 5.99 (s large, 1H, HN9'), 5.17 (2 x s large, 1H, H5) , 3.31 (m, 3H, H2C10' and HC8) , 3.05 (m, 3H, H2C11' and HC8), 2.61 (m, 2H, cyclohexyl), 2.42 (m, 1H, HC12), 2.10-1.25 (m, 7H, 6H, cyclohexyl and HN12'). MS (DCI/NH3 + ) m/z (%) : 566 (11) , 568 (MH+, 100)', 569 (38) , 570 (41) , 571 (12) . Production of trioxaquine dicitrate 4 The trioxaquine 3 (25 mg, 0.04 mmol) is placed in solution in acetone (0.5 ml). Citric acid (17 mg, 2.0 equiv.) in solution in acetone (0.5 ml) is added. The trioxaquine dicitrate precipitates; it is centrifuged, washed twice in diethyl ether and.vacuum-dried. NMR XH (250 MHz, CDC13) 8, ppm: 8.59 (2 x d, 1H, H2 ' ) , 8.30 (2 x d, 1H, H5 ' ) , 7.95 (2 x d, 1H, . H8 ' ) , 7.70 (m, 5H, H6' and 4H phenyl), 7.50 (m, 6H, phenyl), 6.73 (2 x d, 1H, H3'), 6.60 (2 x q, 1H, H6) , 5.42 (2 x s large, 1H, H5) , 3.71 (m, 2H, H2C10' ) , 3.55-3.25 (m, 4H, H2C11', HC8 and HC12) , 3.12 (d, 1H, HC8), 2.76 (d, 4H, citrate), 2.65 (d, 4H, citrate), 2.10-1.50 (m, 8H, cyclohexyl). MS (ES) m/z (%) : in positive mode 568.2 (M+) in negative mode 190.9 (citrate) Elementary microanalysis: for C46H50O17N3CI Theor. %: C 58.01 H 5.29 N 4.41 Exper. %: C 57.65 H 5.09 N 4.49 Example 2: trioxaquine 7 Synthesis of . 7-chloro-4-[N-(3-aminopropyl)amino] - quinoline 5 A mixture of 4,7-dichloroquinoline (5 g, 25 mmol) and 1,3-diaminopropane (9.3 g, 12 6 mmol) is diamine reflux-heated (118°C) for 5 hours with magnetic stirring. After cooling, the solid obtained is reflux-extracted with dichloromethane (3 x 100 ml). The organic phase is washed with distilled water and then dried on sodium sulphate. The concentration of- the dichloromethane phase followed by the addition of hexane precipitate the product in the form of a light yellow solid which is filtered, washed with hexane and vacuum-dried (4.5 g, yield = 76%) . NMR XH (250 MHz,. CDCI3) 5, ppm: 8.48 (d, 2Jm = 5.5 Hz, 1H, H2'), 7.90 (d, 4JHH = 2.2 Hz, 1H, H8 ' ) , 7.70 (d, 3JHH = 8.9 Hz, 1H, H5'), 7.50 (s large, 1H, HN9'), 7.29 I (dd, 3JHH = 8.9 Hz, *Jm = 2.2 Hz, 1H, H6 ' ) , 6.30 (d, 2Jm = 5.5 Hz, 1H, H3'), 3.39 (m, 2H, H2C10'), 3.03 (tr, 2H, H2CII1), 1.87 (m, 2H, tfaCll1), 1.58 (s large, H2N13'). MS (DCI/NH3 + ) m/z (%) : 235 (2), 236 (MH+, 100), 237 (14), 238 (34), 239 (5). Coupling of primary amine with the ketone by reductive amination: production of trioxaquine 6 The ketone 2 (199 mg, 0.55 mmol) and the primary amine 5 (165 mg, 0.70 mmol) are placed in solution in CH2C12 (10 ml) . Sodium triacetoxyborohydride (146 mg, 0.69 mmol) is added. The mixture is kept under stirring at ambient temperature for 15 hours. The reaction medium is then washed with distilled water; the organic phase is dried and the solvent is evaporated to dryness (yield: 96%) .' NMR XH (250 MHz, CDC13) 6, ppm: 8.51 (2 x d, 1H, H2' ) , 8.04 (s large, 1H, HN9'), 1.90 (2 x d, 1H, H8') , 7.80 (2.x d, 1H, H5'), 7.65-7.25 (m, 11H, H6' and 10H phenyl), 6.30 (m, 2H, H3 ' and H6), 5.14 (2 x s large, 1H, H5), 3.39 (q, 2H, H2C10'), 3.29 (d, 1H, HC8), 2.95 (m, 3H, H2C12 ' and HC8) , 2.60 (m, 2H, cyclohexyl), 2.42 (m, 2H, HC12 and HN13'.), 2.10-1.25 (m, 10H, 8H, cyclohexyl and H2C11'). MS (DCI/NH3 + ) m/z (%) : 580 (5), 582 (MH+, 100), 583 (39), 584 (39), 585 (15). Production of trioxaquine dicitrate 7 The trioxaquine 4 (81 mg, 0.14 mmol) is placed in solution in acetone (4 ml) . Citric acid (80 mg, 3.0 equiv.) in solution in acetone (5 ml) is added. The trioxaquine dicitrate precipitates; it is centrifuged, washed twice in diethyl ether and vacuum-dried. NMR XH (250 MHz, DMSO-d6). 5, ppm: 8.60 (2 x d, 1H, H2'), 8.42 (2 x d, 1H, H5 ' ) , 7.93 (2 x d, 1H, H8 ' ) , 7.65 (m, 5H, H6' and 4H phenyl), 7.45 (m, 6H, phenyl), 6.72 (2 x d, 1H, H31), 6.61 (2 x q, 1H, H6), 5.43 (2 x s large, -1H, H5) , 3.8-3.0 (m, 7H, H2C1Q ' , H2C12 ' , HC8 and HC12), 2.76 (d, 4H, citrate), 2.65 (d, 4H, citrate), 2.20-1.40 (m, 10H, 8H cyclohexyl and H2C11'). MS (ES) m/z (%): in positive mode 582.3 (M+) in negative mode 190.8 (citrate) Elementary microanalysis: for C47H52O17N3CI, 1 H20 Theor. %: C 57.35 H 5.53 N 4.27 Exper. %': C57.09H5.20 N4.24 Example 3: trioxaquine 10 Synthesis of 7-chloro-4-[N-(4-aminobutyl)amino]-quinoline 8 A mixture of 4,7-dichloroquinoline (5 g, 25 mmol) and 1,4-diaminobutane (13 ml, 129 mmol) is diamine reflux-heated for 5 hours with magnetic stirring. After cooling, the solid obtained is reflux-extracted with dichloromethane (3 x 100 ml) . The organic phase is washed with distilled water and then dried on sodium sulphate. The concentration of the dichloromethane phase followed by the addition of hexane precipitate the product in the form of a light yellow solid which is filtered, washed with hexane and vacuum-dried (3.4 g, yield = 54%). NMR XH (250 MHz, CDCl3) 5, ppm: 8.50 (d, 3J"HH = 5.5 Hz, 1H, H2'), 7.92 (d, 4JHH = 2.2 Hz, 1H, H8 ') , 7.72 (d, 3J-HH = 8.9 Hz, 1H, H5'), 7.31 (dd, 3JkH = 8.9 Hz, 4JHH = 2.2 Hz, 1H, H6'), 6.36 (d, 3JHH = 5.5 Hz, 1H, H3 ' ) , 6.04 (s large, 1H, flN9' ) , 3.29 (m, 2H, H2C10' ) , 2.81 (tr, 2H, H2C13'), 1.85 (m, 2H, H2C11 ' ) , 1.64 (m, 2H, H2C12 ' ) , 1.45 (s large, H2N14'). MS (DCI/NH3 + ) m/z (%) : 249 (2), 250 (MH+, 100), 251 (18), 252 (36), 253 (5). Coupling of primary amine with the ketone by reductive amination: production of trioxaquine 9 The ketone 2 (170 mg, 0.47 mmol) and the primary amine 8 (150 mg, 0.60 mmol) are placed in solution in CH2C12 (10. ml). Sodium triacetoxyborohydride (125 mg, 0.59 mmol) is added. The mixture is kept under stirring at ambient temperature for 15 hours. The reaction medium is then washed with distilled water; the organic phase is dried and the solvent is evaporated to dryness (yield: 69%). NMR 1H (250 MHz, CDC13) 5, ppm: 8.50 (2 x d, 1H, H2 ' ) , 7.89 (2 x d, 1H, H8 ' ) , 7.78. (2 X d, 1H, H5 ' ) , 7.65-7.25 (m, 11H, H6' and 10H phenyl), 6.35 (m, 2H, H3 ' and H6) , 5.96 (s large, 1H, HN9 ' ) , 5.18 (2 x s large, 1H, H5) , 3.30 (m, 3H, H2C10' and HC8) , 3.00 (2 x d, 1H, JfC8), 2.74 (q, 2H, ff2C13 ' ) , 2.61 (m, 2H, cyclohexyl), 2.46 (m, 1H, HC12), 2.10-1.25 (m, 11H, 6H, cyclohexyl HN14 ' , tf2Cll'and H2C12 ' ) . MS (DCI/NH3 + ) m/z (%) : 596 (MH+) . Production of trioxaquine dicitrate 10 The trioxaquine 9 (51 mg, 0.09 mmol) is placed in solution in acetone (1 ml). Citric acid (33 mg, 2.0 equiv.) in solution in acetone (1 ml) is added. The trioxaquine dicitrate precipitates; it is centrifuged, washed twice in diethyl ether and vacuum-dried. NMR XH (250 MHz, DMS0-d6) 5, ppm: 8.56 (2 x d, 1H H2'), 8.45 (2 x'd, 1H, H5 ' ) , 7.95 (m + 2 x d, 2H, HN9 and H8 ' ) , 7.68 (m, 5H, H6 ' and 4H phenyl), 7.48 (m, 6H, phenyl), 6.72 (2 x d, 1H, H3 ' ) , 6.60 (2 x g, 1H, H6) , 5.41 (2 x s l'arge, 1H, H5) , 3.50 (m, 2H, ff2C10 ') , 3.55-3.10 (m, 5H, H2C13'7 H2C8 ' and HC12), 2.75 (d, 4H, citrate), 2.65 (d, 4H, citrate), 2.10-1.50 (12H, ' 8H cyclohexyl, H2C11' and H2C12 ' ) . MS (ES) m/z (%) : in positive mode 596.2 (M+) ; in negative mode 190.8 (citrate) Elementary microanalysis: for C48H54O17N3CI, 4 H20 Theor. %: C 54.78 H 5.94 M 3.99 Exper. %: C 54.88 H 5.08. ' N 4.06 Example 4: trioxaquines 13a and 13b Synthesis of trioxane functionalised with a ketone 11 A mixture of 1,4-diphenyl-l,3-cyclopentadiene (153 mg, 0.7 mmol) and tetraphenylporphyrine (5 mg) in dichloromethane (5 ml) is irradiated in the presence of molecular oxygen (1.15 bar) for 1 hour, at 5°C, with a white bulb (2 0 0 W) . The peroxide is obtained with a quantitative yield. The unprocessed peroxide in solution in dichloromethane is placed in a bath at -70°C; 4 molar equivalents of cisbicyclo(3.3.0)octane-3,7-dione (410 mg, 3.0 mmol) and 0.4 equivalent of trimethylsilyl trifluoromethane sulphonate , (50 /xl, 0.3 mmol) are added and the reaction mixture is kept under stirring at -70°C for 2 hours. The reaction is stopped by adding triethylamine (100 /xl) . After returning to ambient temperature, the reaction medium is washed with distilled water, dried on magnesium sulphate and evaporated to dryness. Chromatography on silica column' (hexane/ethyl acetate eluent, 70/30, v/v) is used to separate the two isomer trioxanes 11a and lib (overall yield: 42%) . Isomer 11a: NMR XH (250 MHz, CDC13) 5, ppm: 7.60-7.30 (m, 10H, phenyl), 6.29 (dd, ;1H, H6) , 5.27 (s large, 1H, H5) , 3.21 and 3.02 (2 x d, 2J"HH = 17.0 Hz, 2 x 1H, H2C8) , 2.83 (m, 2H) , 2.20 (m, 3H), 1,77 (m, 2H). MS (DCI/NH3 + ) m/z (%) : 406 (MNH4+, 100), 407 (30), 408 (8) . Isomer lib: NMR XH (250 MHz, CDCl3) 5, ppm: 7.60-7.30, (m, 10H, phenyl), 6.32 (dd, 1H, H6) , 5.25 (s large, 1H, H5) , 3.22 and 3.02 (2 x d, 2JHH = 17.0 Hz, 2 x 1H, H2C8) , 2.90 (m, 2H), 2.50-2.15 (m, 7H), 1.79 (m, 1H). MS (DCI/NH3+) m/z (%): 404 (3), 405 (3), 406 (MNH4+, 100), 407 (31), 408 (6), 409 (1). Coupling of primary amine with the ketone by reductive amination: production of trioxaquines 12a and 12b The ketone 11a (163 mg, 0.42 mmol) and the primary amine 1 (120 mg, 0.54 mmol) are placed in solution in CH2C12 (15 ml) . Sodium triacetoxyborohydride (114 mg, 0.54 mmol) is added. The mixture is kept under stirring1 at ambient temperature for several .weeks. The reaction medium is then washed with distilled water; the organic phase is'dried and the solvent is evaporated to dryness (yield: 66%). NMR XH (250 MHz, CDCl3) 5, ppm: 8.42 (d, 1H, H2 ■ ) , 7.86 (d, 1H, H8'), 7.75 (d, 1H, H5 ' ) , 7.65-7.25 (m, 11H, H6' and 10H phenyl), 6.30 (m, 1H, H3 ' ) , 6.23 (m, 1H, H6) , 6.18 (s large, 1H, HN9'), 5.25 (s large, 1H, H5) , 3.57 (s large, 1H, HN12 ' ) , 3.37 (m, 3H, H2C10', HC8) , 3.20 (m, 2H, HC8 and 1H bicyclopentyl), 3.00 (m, 3H, H2C11' and HC8) , 2.75 (m, 1H, bicyclopentyl), 2.45 (m, 2H, HC12 and 1H bicyclopentyl), 2.20 (m, 2H, bicyclopentyl), 1.74-1.10 (m, 5H, bicyclopentyl). MS (DCI/NH3 + ) m/z (%): 594 (MH+) . The ketone lib (148 mg, 0.38 mmol) and the primary amine 1 (110 rag, 0.50 mmol) are placed in solution in CH2C12 (15 ml) . Sodium triacetoxyborohydride (154 mg, 0.73 mmol) is added. The mixture is kept under stirring at ambient temperature for one week. The reaction medium is then washed with distilled water; the organic phase is dried and the solvent is evaporated,to dryness (yield: 68%). NMR XH (250 MHz, CDC13) 8, ppm: 8.48 (d, 1H, H2 ' ) , 7.88 (d, 1H, H8 ' ) , 7.73 (d, 1H, H5 ' ) , 7.65-7.25 (m, 11H, H6.' and 10H phenyl), 6.27 (m, 1H, H3 • and H6) , 6.06 (s large, 1H, HN9'), 5.25 - (s large, 1H, H5) , 3.25 (m, 2H, HaC10'), 3.21 (d, 1H, HC8) , 3.01 (d, 1H, HC8) , 2.94 (m, 3H, H2C11' and 3H bicyclopentyl), 2.54 (m, 3H, HC12 and 2H bicyclopentyl), 2:10 (m, 4H, HN12 ' and 3H bicyclopentyl), 1.77 (m, 1H, bicyclopentyl), 1.25 (m, 3H, bicyclopentyl). MS (DCI/NH3 + ) m/z (%) : 594 (MH+, 100), 595 (44), 596 (44) .' Production of trioxaquine dicitrate 13a and 13b The trioxaquine 12a (166 mg, 0.28 mmol) is placed in solution in acetone (5 ml). Citric acid (160 mg, 3.0 equiv.) in solution in acetone (5 ml) is added. The trioxaquine dicitrate precipitates; it is centrifuged, washed twice in diethyl ether and vacuum-dried. NMR 1H (250 MHZ, CDC13) 5, .ppm: 8.63 (d, 1H, H2 ) 8.40 (d, 1H, H5')., 8.00 (d, 1H, H8 ' ) , 7.70 (m, 5H, H6 ' and 4H phenyl), 7.50 (m, 6H, phenyl), 6.79 (d, 1H, H3 ' ) , 6.60 (q, 1H, H6) , 5.53 (s large,. 1H, H5) , ■ 3.75 (m, 3H, H2C10' and HC8) , 3.3 0 (m, 2H, HC8 and HC12), 3.12 (m, 2H, H2C11'), 2.68 (d, 4H, citrate), 2.39 (m, 4H, citrate), 2.10-1.50 (m, 6H, bicyclopentyl). MS (ES) m/z (%) : in positive mode 594.3 (M+) Elementary microanalysis: for C48H520x7N3Cl, 1 H20 Theor. %: C 57.86 H 5.46 N 4.22 Exper. %: C 58.11 H 5.02 N 4.66 The trioxaquine 12b (153 mg, 0.26 mmol). is placed in solution in acetone (5 ml). Citric acid (160 mg, 3.0 equiv.) in solution in acetone (5 ml) is added. The trioxaquine dicitrate precipitates; it is centrifuged, washed twice in diethyl ether and vacuum-dried. NMR XH (250 MHz, DMSO-dff) §, ppm: 8.60 (d, 1H, H2'), 8.34 (d, 1H, H5 ' ) , 7.95 (d, 1H, H8 ' ) , 7.73 (m, 5H, H6' and 4H phenyl), 7.51 (m, 6H, phenyl), 6.73 (d, 1H, H3 ' ) , 6.'60 (q, 1H, H6), 5.55 (s large, 1H, H5) , 3.69 (m, 3H, H2C10 ' and HC8) , 3.44 (m, 1H, HC12), 3.25. (m, 1H, HC8) , 3.16 (m, 2H, H2C11 ') , 2.77 (d, 4H, citrate), 2.65 (m,' 4H, citrate), 2.55-2.05 (m, 6H, bicyclopentyl), 1.80-1.40 (m, 4H, bicyclopentyl). MS (ES) m/z (%),: in positive mode 594.3 (M+) in negative mode 190.9 (citrate) Elementary microanalysis: for C48H52Oi7N3Cl, 1 H20 Theor. %: .C 57.86 H 5.46 " N 4.22 Exper. %: C 58.19 H 5.05 N 4.17 Example 5: trioxaquines 15a and 15b Coupling of primary amine with the ketone by reductive amination: production of trioxaquines 14a and 14b The ketone 11a (29 mg, 0.075 mmol) and the primary amine 8 (25 mg, 0.10 mmol) are placed in solution in CH2C12 (5 ml) . Sodium triacetoxyborohydride (21 mg, 0.10 mmol) is added. The mixture is kept under stirring at ambient temperature for 48 hours. The reaction medium is then washed with distilled water; the organic phase is dried and the solvent is evaporated to dryness (yield: 64%). NMR 1H (250 MHz, CDC13) 5, ppm: 8.45 (d, 1H, H2 ) 7.92 (d, 1H, -H8'), 7.75 (d, 1H, H5 ' ) , 7.65-7.25 (m, 11H, H6' and 10H phenyl), 6.33 (m, 2H, H3 ' and HN9' ) , 6.27 (m, 1H, H6), 5.25 (s large, 1H, H5), 3.25 (m, 2H, H2C10'), 3.19 (d, 1H, HC8), 3.00 (m, 2H, HC8 and 1H bicyclopentyl), 2.8-2.0 (m, 8H, 4H bicyclopentyl, H2C13', HC12 • and " J3N14 ' ) , 1.75-1.10 (m, 5H bicyclopentyl, H2C11' and H2C12 ') . MS (DCI/NH3 + ) m/z (%) : 622 (MH+) . The ketone lib .(26 mg, 0.070 mmol) and the primary amine 8 (21 mg, 0.084 mmol) are placed in solution in CH2C12 (15 ml) . Sodium triacetoxyborohydride (18 mg, 0.085 mmol) is added. The mixture is kept under stirring at ambient temperature for 48 hours. The reaction medium is then washed with distilled water; the organic phase is dried and the solvent is evaporated to dryness. The mixture obtained contains 70% trioxaquine 12b and is used as is in the next step. NMR XH (250 MHz, CDCI3) 5, ppm.- 8.44 (d, IH, 'H2 ' ) , 7.90 (d, IH, H8'), 7.75 (d, IH, H5 ' ) , 7.65-7.25 (m, 11H, H6' and 10H phenyl), 6.30 (m, 3H, H3 ' , H6 and HN9'), 5.24 (s large, IH, H5) , 3.25 (m, 2H, H2C10 » ) , 3.20 (d, IH, HC8) , 3.00 (m, IH, HC8), 2.85 (m, IH, bicyclopentyl), 2.65-2.0 (m, 9H, 5H bicyclopentyl, H2C13 ' , HC12 and HN14' ) , 1.8-1.6 (m, 5H bicyclopentyl, IH bicyclopentyl, H2C11 and H2C12 ' ) , 1.24 (m, 3H, bicyclopentyl). Production of trioxaquine dicitrates 15a and 15b The trioxaquine 14a (30 mg, 0.05 mmol) is placed in solution in acetone (0.4 ml) . Citric acid (22 mg, 2.4 equiv.) in solution in acetone (0.4 ml) is added. The trioxaquine dicitrate precipitates; it is centrifuged, washed twice in diethyl ether and vacuum-dried. NMR XE (250 MHz, DMSO-d6) 5, ppm: 8.59 (d, IH,. H2' ) , 8.48 (d, IH, H5') , 8.17 (s large, IH, HN9') , 7.97 (d, 1H,.H8'), 7.70 (m, 5H, H6' and 4H phenyl), 7.50 (m, 6H, phenyl), 6.77 (d, IH, H3 ' ) , 6.57 (q, IH, H6) , 5.50 (s large, IH, H5),:3.51 (m, 2H, H2C10 ' and HC8) , 3.10 (m, 4H, H2C13', HC8 and HC12), 2.78 (d, 4H, citrate), 2.67 (m, 4H, citrate), 2.37 (m, 4H, bicyclopentyl)', 2.10-1.50 (m, • 10H, 6H bicyclopentyl, H2C11' and H2C12 ' ) . MS (ES) m/z (%) : in positive mode 622.3 (M+) ' in negative mode 191.2 (citrate) The trioxaquine 14b (28 mg, unprocessed mixture) is placed in solution in acetone (1 ml) . Citric acid (30 mg, 4.0 equiv.) in solution in acetone (2 ml) is added. The trioxaquine dicitrate precipitates; it is centrifuged, washed twice in diethyl ether and vacuum-dried. NMR 1H (250 MHz, DMSO-d6) 8, ppm.- 8.57 (d, 1H, H2'), 8.45 (d, 1H, H5'), 7.93 (d, 1H, H8 ' ) , 7.70 (m, 5H, H6' and 4H phenyl), 7.51 (m, 6H, phenyl), 6.70 (d, 1H, H3 ' ) , 6.61 (q, 1H, H6), 5.52 (s large, 1H, H5) , 4.0-3.0 (m, 7H, H2C10 ' , H2C13 ' , H2C8 andHC12), 2.75 (d, 4H, citrate),. 2.65 (m, 4H, citrate), 2.55-2.05 (m, 6H, bicyclopentyl), 1.90-1.30 (m, 8H, 4H bicyclopentyl, H2C11' and H2C12 ' ) . MS (ES) m/z (%) : in positive mode 622.4 (M+) in negative mode 191.2 (citrate) Example 6: trioxaquine 18 Synthesis of trioxane functionalised with a ketone 16 A mixture of oc-terpinene (420 mg, 3.0 mmol) and tetraphenylporphyrine (5 mg) in,dichloromethane (5 ml) is irradiated in the presence of molecular oxygen (1.15 bar) for 7 hours, at 5°C, with a white bulb (200 W) . The peroxide is obtained with a quantitative yield. The unprocessed peroxide in solution in dichloromethane is placed in a bath at -70°C; 6 'molar equivalents of 1,4-cyclohexadione (2.05 g, 18.3 mmol) and 0.4 equivalent of trimethylsilyl trifluoromethane sulphonate (2 0 0 µl, 1.1 mmol) are added and the reaction mixture is kept under stirring at -70°C for 2 hours. The reaction is stopped by adding triethylam'ine (400 µl) . After returning to ambient temperature, the reaction medium is washed with distilled water, dried on magnesium sulphate and evaporated to dryness. The functionalised trioxane 16 is purified by chromatography on silica column (hexane/ethyl acetate eluent, 85/15, v/v) (yield: 38%);. NMR 1H (250 MHz, CDC13) 5, ppm: 5.40 (m, 1H, H6) , 4.00 (m, 1H, H5) , 2.67 (m, 1H) , 2.41 (m, 4H) , 2.22 (m, 4H), 2.00 (m, 3H) , 1.50 (m, 1H), 0.99 (m, 9H). MS (DCI/NH3 + ) m/z (%) : 297 (26), 298 (MNH4+, 100), 299 (48), 300 (8), 301 (1). Coupling of primary amine with the, ketone by reductive aminatipn: production of trioxaquine 17 The ketone 16 (113 mg, 0.4 0 mmol) and the primary amine 1 (115 mg, 0.52 mmol) are placed in solution in CH2C12 (10 ml) . Sodium triacetoxyborohydride (109 mg, 0.51 mmol) is added. The mixture is kept under stirring at ambient temperature for 20' hours. The reaction medium is then washed with distilled water; the organic phase is dried and the solvent, is evaporated to dryness (yield: 82%) . NMR lH (250 MHz, CDC13) 5, ppm: 8.50 (2 x d, 1H, H2'), 7.92 (2 x d, 1H, H8 ' ) , 7.69 (2 x d, 1H, H5 ' ) , 7.35 (2 x dd, 1H, H6'), 6.36 (2 x d, 1H, H3 ' ) , 5.95 (s large, 1H, HN9 ' ) , 5.41 (m, 1H, H6) , 4.00 (m, 1H, H5) , 3.29 (m, 2H, tf2C10 ' ) , 3.02 (m, 2H, H2C11 ' ) , 2.63 (m, 2H) , 2.43 (m, 1H) , 2.20-1.90 (m, 5H) , 1.85 (m, 5H) , 1.50 (m, 4H), 1.02 (m, 9H). MS (DCI/NH3 + ) m/z (%) : 484 (2), 485 (6), 486 (MH+, 100), 487 (36), 488 (42), 489 (12),-490 (2). Production of trioxaquine dicitrate 16 The trioxaquine 17 (45 mg, 0.09 mmol) is placed in solution in acetone (1 ml) . Citric acid (53 mg, 3.0 equiv.) in solution in acetone (1 ml) is added. The trioxaquine dicitrate precipitates; it is centrifuged, washed twice in diethyl ether and vacuum-dried. NMR XH (250 MHz, DMSO-d6) 5, ppm: 8.62 (2 x d, 1H, H2'), 8.35 (2 x d, 1H, H5 ' ) , 7.97 (2 x d, 1H, H8 ' ) , 7.69 (2 x dd, 1H, H6'), 6.75 (2 x d., 1H, H3 ' ) , 5.45 (m, 1H, H6) , 4.1,7 (m, 1H, H5) , 3.75 (m, 2H, H2C10 ' ) , 3.35 (m, 2H, H2C11'), 3.05 (m, 1H) , 2.76 (d, 4H, citrate), 2.65 (d, 4H, citrate), 2.29 (m, 3H), 2.07 (m, 4H), 1.72 (m, 3H), 1.57 (m, 3H), 1.10 (m, 9H). MS (ES) m/z (%) : in positive mode 486.2 (M+) Theor. %: C 53.84 H 6.03 N 4.83 Exper. %: C 54.2 5 H 5.43 N 5.04 Example 7: trioxaquine 20 Coupling of primary amine with the ketone by reductive amination: production of trioxaquine 19 The ketone 16 (100 mg, 0.36 mmol) and the primary amine 8 (115 mg, 0.46 mmol) are placed in solution in CH2C12 (10 ml) . Sodium triacetoxyborohydride (101 mg, 0.4 8 mmol) is added. The mixture is kept under stirring at ambient temperature for 15 hours. The reaction medium is then washed with distilled, water; the organic phase is dried and the solvent is evaporated to' dryness (yield: 62%). NMR 1H (250 MHz, CDCl3) 5, ppm: 8.47 (2 x d, 1H, H2'), 7.89 (2 x d, 1H, H8 ) , 7.74 (2 X d, 1H, H5 ' ) , 7.35 (2 x dd, 1H, H6'), 6.34 (2 x d, 1H, H3■), 5.9-5.7 (m, 1H, HN9'), 5.39 (m, 1H, H6), 4.00 (m, 1H, H5), 3.27 (m, 2H, H2C10'), 2.70 (m, 2H, H2C13 ' ) , 2.60-2.35 (m, 3H) , 2.30-1.95 (m, 5H) , 1.83 (m, 3H) , 1.67 (m, 4H, H2C11' and Jf2C12'), 1.50 (m, 4H) , 1.00 (m, 9H) . MS (DCI/NH3 + ) m/z (%) : 514 (3), 515 (MH+, 100), 516 (28), 517 (36), 518 (11). Production of trioxaguine dicitrate 20 The trioxaguine 19 (46 mg, 0.09 mmol) is placed in solution in acetone (1 ml) . Citric acid (44 mg, 2.6 eguiv.) in solution in acetone (1 ml) is added. The trioxaguine dicitrate precipitates; it is centrifuged, washed twice in diethyl ether and vacuum-dried. NMR XH (250 MHz, DMSO-dg) 8, ppm: 8.56 (2 x d, 1H, H2 ' ) , 8.45 (2 x' d, 1H, H5 ' ) , 7.95 (2 x'd, 1H, H8 ' ) , 7.67 (2 x dd, 1H, H6'), 6.72 (2 x d, 1H, H3'), 5.45 (m, 1H, H6) , 4.15 (m, 1H, H5) , 3.50 (m, 2H, H2C10 ' ) , 3.20 (m, 1H) , 3.05 (m, 2H, H2C13 ' ) , 2.76 (d, 4H, citrate), 2.65 (d, 4H, citrate), 2.29 (m, 3H), 2.07 (m, 4H), 1.80 (m, 7H) , 1.55 (m, 3H) , 1.10 (m, 9H) . MS (ES) m/z (%): in positive mode 514.4 (M+) Elementary microanalysis: for C41H560i7N3Cl Theor. %: C 54.83 H 6.29 N 4.68 Exper. %: C 54.32 H 5.80 N 4.52 Example 8: trioxaquines 23a and 23b Synthesis of trioxanes functionalised with a ketone 21a, 21b and 21c A mixture of cc-terpinene (320 mg, 2.76 mmol) and tetraphenylporphyrine (5 mg) in dichloromethane (10 ml) is irradiated in the presence , of molecular oxygen (1.15 bar) for 7 hours, at 5°C, with a white bulb (200 W) . The peroxide is obtained with a quantitative yield. The unprocessed peroxide in solution, in dichloromethane is placed in a bath at -70°C; 4 molar equivalents of cisbicyclo(3.3.0)octane-3,7-dione (1.62 g, 11.7 mmol) and .0.5 equivalent of trimethylsilyl trif luoromethane sulphonate (250 µ1, 1.38 mmol) are added and the reaction mixture is kept under stirring at -70°C for 4 hours. The reaction . is stopped by adding triethylamine (4 00 µl) . After returning to ambient temperature, the reaction medium is washed with distilled water, dried on magnesium sulphate and evaporated to dryness. Chromatography on silica column (hexane/ethyl acetate eluent, 70/30, v/v) is used to separate three isomer trioxanes 21a, 21b and 21c, in order of elution (overall yield: 35%). . Isomer 21a: NMR aH (250 MHz, CDC13) 5, ppm: 5.37 (d large, 1H, H6) , 3.85 (d large, 1H, H5) , 3.10-2.60 (m, 3H) , 2.48 (m, 2H) , 2.16 (m, 6H), 1.90-1.40 (m, 4H), 0.99 (m, 9H). MS (DCI/NH3 + ) m/z (%) : 323 (4), 324 (MNH4+, 100)., 325 (21), 326 (5). Isomer 21b: NMR aH (250 MHz, CDCl3) 5, ppm: 5.38 (d large, 1H, H6) , 3.88 (d large, 1H, H5) , 2.82 (m, 2H) , 2.62 (m, - 1H) , 2.5-2.0 (m, 10H) , 1.72 (m, 1H) , 1.49 (m, 1H) , 0.99 (m, 9H) . . MS (DCI/NH3 + ) m/z (%) : 323 (14), 324 (MNH4 + , 100), 325 (23), 326 (5), 327 (1). Isomer 21c: NMR XH (250 MHz, CDCl3) 5, ppm: 5.23 (m, 1H, H6) , 4.40 (m, 1H, H5) , 3.10-2.6 (m, 3H) , 2.49 (m, 2H) , 2.17 (m, 6H) , 1.9-1.5 (m, 4H) , 1.37 (s, 3H) , 1.00 (m, 6H) . MS (DCI/NH3 + ) m/z (%) : 323 (26) , 324 (MNH4+, 100) , 325 (19), 326 (5), 327 (1). Coupling of primary amine with the ketone by reductive amination: production of trioxaquines 22a and 22b The ketone 21a (70 mg, 0.23 mmol) and the primary amine 1 (66 mg, 0.30 mmol) are placed in solution in CH2C12 (5 ml) . Sodium triacetoxyborohydride (61 mg, 0.29 mmol) ' is added. The mixture is kept under stirring at ambient temperature for one week. The 'reaction medium is then washed with distilled water; the organic phase is dried and the solvent is evaporated to dryness (yield: 70%). NMR XE (250 MHz, CDC13) 5, ppm: 8.45 (d, 1H, H2 ' ) , 7.85 (d, 1H, H8'), 7.70 (d, 1H, H5 ' ) , 7.29 (dd, 1H, H6'), 6.31 (d, 1H, H3'), 6.09 (s large, 1H, J£N9 ' ) , 5.36 (d large, 1H, H6) , 3.87 (d large, 1H, H5), 3.31 (m, 2H, H2C10')., 3.11 (m, 2H) , 2.99 (m, 2H, H2C11 ' ) , 2.75-2.35 (m, 3H), 2.20 (m, 6H), 1.90-1.40 (m, 4H), 1.21 (m, 2H), 0.98 (m, 9H). MS (DCI/NH3 + ) m/z (%) : 512 (MH+, 100), 513 (32), 514 (46), 515 (15), 516 (7). The ketone 21b (35 mg, 0.11 mmol) and the primary amine 1. (32 mg, 0.14 mmol) are placed in solution in CH2C12 (5 ml) . Sodium triacetoxyborohydride (3 0 mg, 0.14 mmol) is added/ The mixture is kept under stirring at ambient temperature for several weeks. The reaction medium is then washed with distilled water; the organic phase is dried and the solvent is evaporated to dryness (yield: 75%). NMR XH (250 MHz, CDC13) 5, ppm: 8.46 (d, 1H, H2 ■ ) , 7.90 (d, 1H, H81), 7.76 (d, 1H, H5' ) , 7.35 (dd, 1H, H6'), 6.34 (d, 1H, H3'), 6.03 (s large, 1H, HN9'), 5.42 (d large, 1H, H6), 3.89 (d large, 1H, H5), 3.26 (m, 2H, H2C10'), 2.97 (m, 3H, H2C11 ' and 1H) , 2.7-1.9 (m, 11H) , 1.70 (m, 2H), 1.50 (m, 2H) , 1.24 (m, 2H) , 0.98 (m, 9H) . MS (DCI/NH3 + ) m/z (%): 510 (10), 512 (MH+, 100), 513 (35), 514 (51), 515 (16), 516 (7). Production of trioxaquine dicitrates 23a and 23b The trioxaquine 22a (82 mg, 0.16 mmol) is placed in solution in acetone (5 ml) . Citric acid (90 mg, 2.9 equiv. ) in solution in acetone (5 ml) is added. The trioxaquine dicitrate precipitates; it is centrifuged, washed,twice in diethyl ether and vacuum-dried. NMR XH (250 MHz, DMSO-d*) 5, ppm: 8.62 (d, 1H, H2'), 8.40 (d, 1H, H5'), 7.97 (d, 1H, H8 ' ) , 7.69 (dd, 1H, H6'), 6.78 (d, 1H, H3 ' ) , 5.49 (d large, 1H, H6) ■, 4.02 (d large, 1H, H5), 3.78 (m, 2H, H2C10'), 3.65 (m, 1H), 3.32 (m, 2H, H2C11'), 2.79 (d, 4H, citrate), 2.68 (d, 4H, citrate), 2 .-60-1.90 (m, 9H) , 1.80 (m, 4H) , 1.10 (m, 9H) . MS (ES) m/z (%) : in positive mode 512.3 (M+) in negative mode 190.8 (citrate) Elementary microanalysis: for C4iH54017N3,Cl Theor. %: C 54.95 H 6'. 08 N 4.69 Exper. %: C 55.07 H 6.15 N 4.52 The trioxaquine 22b (44 mg, 0.09 mmol) is placed in solution in acetone (4 ml). Citric acid (50 mg, 3.0 equiv.) in solution in acetone (4 ml) is added. The trioxaquine dicitrate precipitates; it is centrifuged, washed twice in diethyl ether and vacuum-dried. NMR aH (250 MHz, DMS0-d6) 5, ppm: 8.62 (d, 1H, H2'), 8.36 (d, 1H, H5 ' ) , 7.96 (d, 1H, H8 ' ) , 7.70 (dd, 1H, H6'), 6.75 (d, 1H, H3 ' ) , 5.48 (d large, 1H, H6) , 4.05 (d large, 1H, H5), 3.73 (m, 2H, H2C10'), 3.45 (m, 1H), 3.29 (m, 2H, H2C11' ) , 2.80 (d, 4H, citrate), 2.68 (d, 4H, citrate), 2.31 (m, 6H) , 2.06 (m, 4H) , 1.8-1.4 (m, 5H), 1.10 (m, 9H). MS (ES) m/z (%) : in positive mode 512.5 (M+) in negative mode 191.2 (citrate) Elementary microanalysis: for C4iH54017N3Cl, 2 H20 Theor. %: C 52.81 H 6.2 7 .' N 4.51 Exper. ,1: ' C 52.93 H 5.49 N 5.18 Example 9.- trioxaquines 25a and 25b Coupling of primary amine with the ketone by reductive amination: production of trioxaquines 24a and 24b The ketone 21a (70 mg, 0.23 mmol) and the primary amine 8 (71 mg, 0.28 mmol) are placed in solution in CH2C12 (5 ml) . Sodium triacetoxyborohydride (61 mg, 0.29 mmol) is added. The mixture is kept under stirring at ambient temperature for. one week. The reaction medium is then washed with distilled water; the organic , phase is dried and the solvent is evaporated to dryness (yield: 51%). NMR XH (250 MHz, CDC13) 5, ppm: 8.49 (d, 1H, H2 ' ) , 7.92 (d, 1H, H8'), 7.74 (d, 1H, H5 ' ) , 7.32 (m, 1H, H6'), 6.35 (m, 1H, H3), 6.0-5.8 (m, 1H, HN9'), 5.39 (d large, 1H, H6) , 3.88 (d large, 1H, H5) , 3.26 (m, 2H, H2C10'), 2.91 (m, 2H) , 2.68 (m, 2H, H2C11 ' ) , 2.48 (m, 3H) , 2.20 (m, 6H) , 1.90-1.40 (m, 8H) , 1.22 (m, 2H) , 0.97 (m, 9H). MS (DCI/NH3 + ) m/z (%) : 538 (7) , 539 (5) , 540 (MH+, 100), 541 (37), 542' (70), 543 (21), 544 (13). The ketone 21b (3 5 mg, 0.11 mmol) and the. primary amine 8 (40 mg, 0.16 mmol) are placed in solution in CH2C12 (5 ml) . Sodium triacetoxyborohydride (33 mg, 0.16 mmol) is added. The mixture is kept under stirring at ambient temperature for several weeks. The reaction medium is then washed with distilled water; the organic phase is! dried and the solvent is evaporated to dryness (yield: 76%). NMR XE (250 MHz, CDCl3) 5, ppm: 8.48 (d, 1H, H2 ' ) , 7.90 (d, 1H, H8'), 7.75 (d, 1H, H5 ' ) , 7.33 (dd, 1H, H6'), 6.33 (d, 1H, H31), 6.02 (s large, 1H, HN9'), 5.41 (d large, 1H, H6), 3.90 (d large, 1H, H5), 3.25 (m, 2H, H2C10'), 2.93 (m, 1H) , 2.67 (m, 2H, H2C11 ' ) , 2.45 (m, 3H) , 2.20 (m, 6H) , 2.00 (m, 2H) , .1.8-1.6 (m, ' 6H) , 1.48 {m> 1H), 1.25 (m, 2H), 1.00 (m, 9H). MS (DCI/NH3+) m/z (%) : 538 (10), 539 (9), 540 (MH+, 100), 541 (40), 542 (40),. 542 (67), 543 (23), 544 (14). Production of trioxaquine dicitrates 25a and 25b The trioxaquine 24a (63 mg, 0.12 mmol) is placed in solution in acetone (5 ml) . Citric acid (70 mg, 3.0 equiv.) in solution in acetone (5 ml) is added. The trioxaquine dicitrate precipitates; it is centrifuged, washed twice in diethyl ether and vacuum-dried. NMR XH (250 MHz, DMS0-d6) 5, ppm: 8.58 (d, IH, H2' ) , 8.49 (d, IH, H5') , 8.14 (s large, IH, HN9') , 7.97 (d, IH, H8'), 7.70 (dd, IH, H6 ' ) , 6.77 (d, IH, H3 ' ) , 5.48 (d large, IH, H6) , 4.03 (d large, IH, H5) , 3.50 (m, 2H, H2C10'), 3.36 (m, IH) , 3.04 (m, 2H, H2C13 ' ) , 2.75 (d, 4H, citrate), 2.65 (d, 4H, citrate), 2.60-1.95 (m, 9H) , 1.90-1.45 (m, 10H) , 1.10 (m, 9H) . MS (ES) m/z (%) : in positive mode 540.3 (M+) in negative mode 191.2 (citrate) Elementary microanalysis: for C43H58O17N3CI Theor. %: C 55.88 H 6.33 N 4.55 Exper. %: C'55.35 H 6.27 N 4.37 The trioxaquine 24b (47 mg, 0.09 mmol) is placed in solution in acetone (4 ml). Citric acid (50 mg, 3.0 equiv.) in solution in acetone (4 ml) is added. The trioxaquine dicitrate precipitates; it is centrifuged, washed twice in diethyl ether and vacuum-dried. NMR XH (250 MHz, DMSO-d6) §, ppm: 8.58 (d, IH, H2'), 8.45 (d, IH, H5'), 8.01 (s large, IH, £N9'), 7.95 (d, IH, H81), 7.69 (dd, IH, H6' ) , 6.75 (d, IH, H3 ) , 5.47 (d large, IH, H6) , 4-.05 (d large, IH, H5) , 3.48 (m, 2H, H2C10'), 3.35 (m, 1H) , 3.03 (m, 2H, H2C13 ' ) , 2.76 (d, 4H, citrate), 2.65 (d, 4H, citrate), 2.30 (m, 6H) , 2.06 (m, 4H) , 1.9-1.4 (m, 9H) , 1.09 (m, 9H) . MS (ES) m/z (%) : in positive mode 540.4 (M+) in negative mode 191.0 (citrate) Elementary microanalysis: for C43H58O17N3Cl, 1 H20 Theor. %: C 54.80 H 6.42 N 4.46 Exper. %: C 54.93 H 6.01 N 4.44 Example 10.- trioxaquines 28a and 28b Synthesis of trioxanes functionalised with a ketone 2 6a and 2 6b A mixture of 1,3-cyclohexadiene (4 0 0 mg, 5 mmol) and tetraphenylporphyrine (5 mg) in dichloromethane (10 ml) is irradiated in the presence of molecular oxygen (1.15 bar) for 1 hour, at 5°C, with a white bulb (200 W) . The peroxide is obtained with a quantitative yield. The unprocessed peroxide in solution in dichloromethane is placed in a bath at -70°C; 4 molar equivalents of 1,4 cyclohexanedione (2.3 g, 2 0 mmol) and 0.4 equivalent of trimethylsilyl trifluoromethane sulphonate (500 µl, 2.8 mmol) are added and the reaction mixture is kept under stirring at -70°C for- 4 hours. The reaction is stopped by adding triethylamine (1000 ill) . After returning to ambient temperature, the reaction medium is washed with distilled water', dried on magnesium sulphate and evaporated to dryness. Chromatography on silica column (hexane/ethyl acetate eluent, 70/30, v/v) is used to separate the two isomer trioxanes 26a and 26b (overall yield: 2%). Isomer 26a: NMR 1H (250 MHz, CDCl3) 5, ppm: 5.70 (m, 1H, H6) , 5.57 (m, 1H, H7) , 4.50 (m, 1H, H5) , 4.25 (ddd, 1H, H10) , 2.68 (m, 1H) , 2.45 (m, 5H) , 2.32 (m, 2H) , 2.03 (m, 2H) , 1.90 (m, 1H) , 1.55 m, 1H) . . . MS (DCI/NH3 + ) m/z (%): 241 (2), 242 (MNH4\ 100), 243 (16) , 244 (5) . Isomer 2 6b: NMR 1H (250 MHz, CDC13) 5, ppm: 6.00 (m, 1H) , 5.73 (m, 1H) , 4.50 (m, 1H) , 4.20 (m, 1H) , 2.60-1.80 (m, 12H) . MS (DCI/NH3 + ) m/z (%) : 241 (2), 242 (MNH4+, 100), 243 (17), 244 (5). Coupling of primary amine with the ketone by reductive amination- production of trioxaquines 2 7a and 2 7b The ketone 2 6a (9 mg, 0.04 mmol) and the primary amine 1 (12 mg, 0.05 mmol) are placed in solution in CH2C12 (3 ml) . Sodium triacetoxyborohydride (21 mg, 0.10 mmol) is added. The mixture is kept under stirring at ambient temperature for 15 hours. The reaction medium is then washed with distilled water; the organic phase is dried and the solvent is evaporated to dryness (yield: 35%). NMR XH (250 MHz, CDC13) 5, ppm: 8.49 (d, 1H, H2 ' ) , 7.93 (2 x d, 1H, H8'), 7.75 (2 x d, 1H, H5' ) , 7.37 (m, 1H, H6'), 6.35 (m, 2H, H3 ' and HN9' ) , 5.66 (d large,. 1H, H6) , 5.55 (d large, 1H, H7) ; 4.48 (d large, 1H, . H5), 4.15 (d large, 1H, H10), 3.38 (m, 2H, H2C10 ' ) , 3.10 (m, 2H, H2C11'), 2.67 (m, 2H) , 2.49 (m, 3H) , 2.30 (m, 2H) , 2.10-1.30 (m, 7H) . MS (DCI/NH3 + ) m/z (%): 430 (MH+, 100), 431 (30), 432 (47) . The ketone 26b (7 mg, 0.03 mmol) and the primary amine 1 (15 mg, 0.07 mmol) are placed in solution in CH2C12 (5 ml) . Sodium triacetoxyborohydride (12 mg, 0.06 mmol) is added. The mixture is kept under stirring at ambient temperature for one week. The reaction medium is then washed with distilled water; the. organic phase is dried and the solvent is evaporated to dryness (yield: 45%). NMR XH (250 MHz, CDCl3) 5, ppm: 8.50 (2 x d, 1H, H2 ) , 7.92 (2 x d, 1H, H8 ' ) , 7.70 (2 x d, 1H, H5 ' ) , 7.36 (2 x dd, 1H, H6'), 6.34 (2 x d, 1H, H3'), 6.06 (s large, 1H, HN9'), 5.99 (m, 1H, H6), 5.72 (m, 1H, H7) , 4.41 (m, 1H) , 4.10 ' (m, 1H) , 3.32 (m, 2H, H2C10') , 3.05 (m, 2H, H2C11'), 2.63 (m, 2H) , 2.30 (m, 4H) , 2.10 (m, LH), 2.00-1.35 (m, 7H). MS (DCI/NH3 + ) m/z (%) : 428 (15), 429 (9), 430 (MH\ 100), 431 (30), 432 (49), 433 (14). Production of trioxaquine dicitrate 2 8b The trioxaquine' 27b (6 mg, 0.014 mmol) is placed in solution in acetone (1 ml). Citric acid (10 mg, 3.7 equiv.) in solution in acetone (1 ml) is added. The trioxaquine dicitrate precipitates; it is centrifuged, washed twice in diethyl ether and vacuum-dried. NMR XH (250 MHz, DMSO-d6) 5, ppm: 8.65 (d, 1H, H2 ' ) , 8.37 (d, 1H, H5' ) , 7.98 (d, 1H, H8 ' ) , 7.69 (dd 1H, H6»), 6.75 (d, 1H, H3 ' ) , 6.05 ' (m, 1H) , 5.80 (m, 1H) , 4.57 (m, 1H) , 4.30 (m, 1H) , 3.75 (m, 2H, H2C1Q ') , 3.34 (m, 3H, H2C13 ' and 1H) , 2.80 (d, 4H, citrate), 2.68 (d, 4H, citrate), 2.50-1.50 (m, 12H) . MS (ES) m/z (%) : in positive mode 430.2 (M+) in negative mode 191.2 (citrate) ' Elementary microanalysis: for C35H44017N3C1 Theor. %: C 51.65 H 5.45 N 5.17 Exper. %: C 51.69 H 5.18 N 4.66 Example 11: trioxaquine 32 Synthesis of oxoaldehyde 4-oxopentanal 2 9 To a suspension of pyridinium chlorochromate PCC (6.4 g, 3 0 mmol) in dichloromethane (25 ml) 3-acetylpropan-1-ol (2.0 g, 20 mmol) is slowly added. The reaction mixture is left under stirring at ambient temperature for 2 hours and is then filtered on a silica gel with ether. The_ black residue is washed twice with ether and the filtered ether-treated phases are pooled and evaporated. The aldehyde is obtained in the form of dark liquid (80% purity, 84% yield). NMR XH (250 MHz, CDC13) 5, ppm: 9.75 (S, 1H) , 2.70 (s large, 4H) , 2.14 (s, 3H).. Synthesis of trioxane functionalised with a ketone 30 A mixture of 2,3-dimethylbut-2-ene (270 mg, 3.2 mmol) and tetraphenylporphyrine (5 mg) in dichloromethane (5 ml) is irradiated in the presence of molecular oxygen (1.15 bar) for 7 hours, at 5°C, with a white bulb (200 W) . The peroxide is obtained with a quantitative yield. The unprocessed peroxide in solution in dichloromethane is placed in a bath at - 70°C; 10 molar equivalents of 4-oxopentanal 29 (2.2 mg, 22 mmol) and a few drops of trif luoroacetic acid CF3COOH are added. The mixture is stirred at ambient temperature for 90 minutes and then 2 equivalents of N-iodosuccinimide (1.35 g, 6 mmol) are added and the mixture: is kept under stirring and protected from light for 3 hours, after which the reaction medium is washed with 20% sodium thiosulphate followed by distilled water. After drying on sodium sulphate and evaporation to dryness, the functionalised trioxane 3 0 is purified by chromatography on alumina column (hexane/ether eluent, 50/50, v/v) (yield: 14%).. NMR XH (250 MHz, CDC13) 5, ppm: 5.39 (t, 1H, H3) , 3.31 (d, 2JHH = 11 Hz, 1H, HC10) , 3.12 (d, 2JHH ='11 Hz, 1H, HC10), 2.55 (m, 2H, H2C12) , 2.15 (s, 3H, H3C14), 1.83 (m, 2H, H2C11) , 1.48 (2 s, 6H, H3C8 and H3C7) , 1.06 (s, 3H, H3C9) . MS (DCI/NH3 + ) m/z (%) : 359 (22), 360 (MNH4 + , 100), 361 (14) , 362 (2) . Coupling of primary amine with the ketone by reductive amination: production of trioxaquine 31 The ketone 30 (13 mg, 0.04 mmol) and the primary amine 1 (15 mg, 0.07 mmol) are placed in solution in CH2C12 (4 ml). Sodium triacetoxyborohydride (11 mg, 0.05 mmol) is added. The mixture is kept under stirring at ambient temperature for 7 days. The reaction medium is then washed with distilled water; the organic phase is dried and the solvent is evaporated to dryness (yield: 59%). NMR XH (250 MHz, CDCl3) 5, ppm: 8.50 (d, IH, H2 ' ) , 7..95 (d, IH, H8'), 7.72 (d, IH, H5 • ) , 7.39 (2 x dd, IH, H6'), 6.37 (2 x d, IH, H3 ' ) , 6.00 .(s large, IH, HN9 • ) , 5.37 (t, IH, H3), 3.30 (m, 3H, H2C10 ' and HC10) , 3.11 (d, 2JHH '= 11 Hz, IH, HC10) , 3.00 (m, 2H, H2C11 ' ) , 2.74 (m, IH, HC13), 1.8 (s large, IH, HN12'), 1.65-1.55 (m,> 4H, H2C11 and ff2C12), 1.50 (2 s, 6H, H3C8 and H3C7) , 1.10 (d, 3H, H3C14) , 1.05 (s, 3H, H3C9) . MS (DCI/NH3 + ) m/z (%) : 547 (6), 548 (MH+, 100), 549 (29) , 550 (37) , :551 (9) . Production of trioxaquine dicitrate 32 The trioxaquine 31 ('40 mg, 0.073 mmol) is placed in solution in acetone (1 ml) . Citric acid (52 mg, 3.7 equiv.) in solution in acetone (1 ml) is added. The trioxaquine dicitrate precipitates; it is centrifuged, washed twice in diethyl ether and vacuum-dried. NMR XH (250 MHz, DMSO-d&) 8, ppm: 8.63 (d, IH, H2 ) , 8.37 (d, IH, H5 ' ) , 7.99 (d, IH, H8 ' ) , 7.71 (dd, IH, H6'), 6.77 (d, IH, H3' ) , 5.37 (t, IH, H3), 3.7 (m, 4H, H2C10', HC10 and HC13), 3.34 (m, 3H, H2C11 and HC10), 2.78 (d, 4H, citrate), 2.67 (d, 4H, citrate), 2.0-1.6 (m, 4H), 1.54-1.35 (m, 6H), 1.22 (m, 6H). MS (ES) m/z (%) : in positive mode 548.2 (M+) in negative mode 191.2 (citrate) Elementary microanalysis: for C34H47O17N3CI Theor. %: C 43.81 H 5.08 N 4.51 Exper. %: C 44.08 H 4.69 N 4.72 Example 12: trioxaquine 34 Coupling of primary amine with the ketone by reductive amination:' production of trioxaquine 33 The ketone 30 • (23 mg, 0.07 mmol) and the primary amine 8 (27 mg, 0.11 mmol) are placed in solution in CH2C12 (5 ml) • Sodium triacetoxyborohydride (27 mg, 0.13 mmol) is added. The mixture is kept under stirring at ambient temperature for 10 days. The reaction medium is then washed with distilled water; the. organic phase is dried and the solvent is evaporated to dryness (yield: 10%). NMR XE (250 MHz, CDCl3) 5, ppm: 8.50 (d, 1H, H2 ' ) , 7.90 (d, 1H, H8'), 7.75 (d, 1H, H5'), 7.34 (2 x dd, 1H, H6'), 6.38 (2 x d, 1H, H3 ' ) , 6.00-5.70 (s large, 1H, HN9') , 5.35 (t, 1H, H3) , 3.30 (m, 3H, H2C10' andHCIO), 3.11 (d, 2JHH = 11 Hz, 1H, HC10), 2.71 (m, 2H, H2C13 ' ) , 2.51 (m, 1H, HC13), 1.78 (m, 4H), 1.65 (m, 4H), 1.48 (2 s, 6H, H3C8 and H3C7) , 1.25 (m, 3H),1.09 (s,.3H, H3C9) . MS. (DCI/NH3 + ) m/z (%) : 576 (MH+) . Production of trioxaquine dicitrate 34 The trioxaquine 33 (20 mg, 0.035 mmol) is placed in solution in acetone (1 ml). Citric acid (24 mg, 4.5 equiv.) in solution in acetone (1 ml) is added. The trioxaquine dicitrate precipitates; it is centrifuged, washed twice in diethyl ether and.vacuum-dried. NMR 2H (250 MHz, DMSO-d5) 5, ppm: 8.62 (d, 1H, H2'), 8.46 (d, 1H, H5' ) , 7.96 (m, 2H, H8 ' and HN9' ) , 7.70 (m, ' 1H, H6'), 6.73 (d, 1H, H3 • ) , 5.50 (t, 1H, H3), 4.0-3.0 (m, 7H, H2C10 ' , H2C13, H2C10 and HC13), 2.77 (d, 4H, citrate), 2.66 (d, 4H, citrate), 1.9-1.6 (m, 8H), 1.53 (m, 6H) , 1.4-1.1 (m, 6H) . MS .'(ES) m/z (%) : in positive mode 576.2 (M+) Example 13: Study -of the anti-malarial activity of trioxaquines on P. falciparum. The in vitro results obtained on P. falciparum cultured in human red blood cells are given below. Experimental section The P. falciparum strains are cultured continuously according to Trager and Jensen's method 5, with the following modifications 6: the parasites are maintained in human red blood cells (0±), diluted to 1% haematocrit in RPMI 1640 medium supplemented with 25 mM Hepes + 30 mM NaHC03 and complemented with 5% AB+ human serum. The parasite populations are synchronised over a 4 hour period by flotation with a gelatine solution, followed by lysis with 5% D-sorbitol 7,8. The Nigerian strain is considered to be susceptible to chloroquines and the FcM29-Cameroon and FcBl-Columbia strains are chloroquine-resistant (IC50 for chloroquine 100 nM) 9,10. The anti-malarial activity tests are performed using Desjardins' radioactive micromethod 11. The tests are performed in triplicate, in '96-well microplates, the reading's being at 1% haematocrit and 0.5-1% parasitaemia. For each test, the parasites are incubated with decreasing concentrations of drug for either . 32 hours and 72 hours (4 wells contain chloroquine diphosphate as a reference). The first dilution of the drug is performed at 10 mg/ml in dimethylsulphoxide and the following dilutions are made with RPMI 1640. The parasite growth is measured with the incorporation of tritiated hypoxanthine compared to incorporation in the absence of drug (taken to be 100%) . 12 and the IC50 values are determined graphically by plotting the percentage of inhibition as a function of the drug concentration. The IC50 values measured after 3 2 hours, equivalent to the end of the trophozoite stage, are used to evaluated the influence of the compound on parasite maturation, the IC50 values measured after 72 hours, corresponding to 1.5 of the life cycle in red blood cells, indicate a possible effect on erythrocyte reinvasion. Trioxaquine structures tested: Results Trioxaquines 9, 3 and 6 and trioxaquine citrate 4 were tested independently on the Nigerian, FcBl and FcM29 .strains; the results obtained were compared to those of chloroquine diphosphate and to those of two trioxaquine fragments: quinoline-amine 1 (n=2) and trioxane-ketone 2. The results are summarised in the following table: Table. IC50 values measured for 9, 3, 6, 4 tested independently on three Plasmodium falciparum strains. FcBl- FcM29- Nigerian Colombia Cameroon (CQS)a (CQR)a " (CQR+)a 32 72 32 72 32 72 hrs hrs hrs hrs hrs ■ hrs 6 ng/ml 40 35 25 10 50 50 (n=3) nM 69 60 43 17 86 86 9 ng/ml 16 10 22 20 20 20 (n=4) nM 27 17 37 34 34 34 3 ng/ml 15 5 18 10 1 1 (n=2) nM 26 9 32 18 1.8 1.8 4 ng/ml 35 20 n.d.b- n.d.b 33 7 (n=2), citrate nM 37 21 35 ' 8 Quinol: ine- ng/ml 35 20 n.d.b n.d.b 33 7 amine1 Trioxane- nM 113 36 n.d.b n.d.b 149 45 ketone 2 Chloroquine ng/ml 75 60 .100 80 45 10 diphosphate0 nM 145 116 194 155 87 19 CQR = chloroquine resistant strain. CQR + = highly chloroquine resistant strain, CQS = chloroquine susceptible strain. b Not determined. c Given for, comparison purposes. The IC50 values obtained for the compounds 3, 4, 6 and 9 are between 5 and 5 0 ng/ml, which is equivalent to a concentration of 8 to 86 nM. All the trioxaquine samples are more active than chloroquine, on both susceptible and resistant strains (except for 6 on the Nigerian susceptible strain). The high efficacy of 9, 3 and 4 on the susceptible and resistant, strains, significantly greater than the activity of not .only chloroquine, but also of each of, the two fragments, guinoline-amine 1 (n=2) and trioxane-keto.ne 2, indicates a significant synergic effect between the trioxane and chloroquinoline fragments of these compounds. The citrate form of compound 4 increases its solubility considerably in aqueous media while retaining a high activity. Protonation by other acids than citric acid produces salts offering the same advantages (hydrochloride, sulphate, tartrate). The low IC5Q values obtained with trioxaqui'ne 3 on the FcBl, FcM2 9 strains and on the Nigerian strain (9 nM, 18 nM and 1.8 nM respectively) and with 9 and the citrate 4, indicate that the efficacy of these compounds is retained for a wide spectrum of parasites. Example 14: Preparation of pharmaceutical formulations based on molecules according to the invention. - in the form of scored tablets . active ingredient: 100 mg . excipients: starch, hydrated 'silica, amylaceous ground sugar, gelatine, magnesium stearate. - in the form of film-coated tablets . active ingredient: 300 mg excipients: Core: wheat starch, amylaceous ground sugar (sucrose powder supplemented with starch), hydrated silica,, gelatine, magnesium stearate. Coating: methylhydroxy propylcellulose, poloxyethyleneglycol 20 000. - in the form of syrups . active ingredient: 25 mg/ml excipients: citric acid, sucrose, coffee extract, caramel,, purified water. - in the form of solutions for injection . active ingredient: 100 mg for one 1 ml ampoule, 2 00 mg for one 2 ml ampoule, 400 mg for one 4 ml ampoule. excipients: sodium chloride and water for injections. - in the form of 25% solutions for injection . active ingredient: 500 mg excipients: lactic acid (solubilising agent), formic acid, water for injections. Preservative: anhydrous sodium sulphite equivalent to 0.61 mg sulphur anhydride/amp. - in the form of 100 mg/ml oral suspensions: . active ingredient: 20 mg/ml. excipients: microcrystalline cellulose and sodium .carboxymethylcellulose, propylene glycol', sorbitol, anhydrous citric acid, sodium citrate, sodium benzoate, banana-vanilla flavour, dimethylpolysiloxane emulsion, purified water. Example 15 Activity of trioxaquine-citrate 4 on human isolates Trioxaquine-citrate 4, referred to as DU-1102, was tested on human Plasmodium falciparum isolates, some of which were chloroquine- and/or pyrimethamine-resistant. The median inhibitory concentration values, ■ IC50, obtained are 11 to 68 ng/ml, corresponding to a geometric mean of 41 ng/ml, i.e. 43 nM. The activity of DU-1102 on these isolates is independent of their susceptibility or their resistance to the other anti-malarial agents tested. There is no correlation between DU-1102 on the one hand and chloroquine or pyrimethamine on the other, which indicates the absence of the probability of cross-resistance between DU-1102 and said anti-malarial agents already used. These results indicate the satisfactory efficacy of trioxaquines on wild P. falciparum strains. Activity of trioxaquine-citrate DU-1302, represented below: 2.1. In vitro, this compound shows an activity, LC50 = 6 nM on P. falciparum in culture. 2.2. The trioxaquine citrate DU-13 02 is active in vivo in mice infected with P. vinckei ("4 day" test: treatment for 4 consecutive days starting 24 hours after inoculation of the parasite). - ED50 = 5 mg/kg/day, or 6 µmol/kg/day, by the intraperitoneal route, with no observable re-emergence for 2 months, - ED50 = 18 mg/kg/day, or 2 0 µmol/kg/day, by the oral route. 2.3. The trioxaquine-citrate DU-1302 does not show any apparent toxicity after administration to healthy mice, at a dose of 100 mg/kg/day by the oral route, for three consecutive days. 3. Absence of mutagenicity of trioxaquine-citrates DU-1102 and DU-1302. The above two compounds do not induce DNA repair (no SOS response in E. coli GE864 at concentrations of 5, 10, 15 and 20 µM: the control used is 3 µM mitomycin C) . Therefore, they are non-mutagenic for E. coli at these concentrations. formulas of compounds for which the synthesis is described in the examples WE CLAIM: 1. Dual molecules characterized in that they consist of coupling products having the formula (I) wherein -A represents a residue of molecule with anti-malarial activity, -Y1 and Y2, identical or different, represent a linear or ramified alkylene chain at CI to C5, containing if applicable one or more amine, amide, sulphonamide, carboxyl, hydroxyl, ether or thioether radicals, said alkylene chain at C1 to C5 being substituted if applicable by an alkyl radical at C1 to C5, with the possibility of either Y1 or Y2 being absent, -U is an amine, amide, sulphonamide, carboxyl, ether or thioether function, said function linking Y1 and Y2, -Z1 and Z2, identical or different, represent a saturate or unsaturated, linear, ramified or cyclic arylene or alkylene radical, with the possibility of either Zi or Z2 being absent, or Z1 + Z2 together represent a polycyclic structure including the junction carbons Ci and Cj, -R1 and R2, identical or different, represent a hydrogen atom or a functional group capable of increasing the hydro solubility of the dual molecule, advantageously selected from -COOH, -OH, -N(Ra, Rb) where Ra and Rb, identical or different, represent a hydrogen atom or an alkyl radical at C1 to C5. -Rx and Ry, form a cyclic peroxide with 4 to 8 chain links, which may comprise 1 or 2 additional oxygen atoms in the cyclic structure, Cj being one of the peaks of said cyclic peroxide, or -Rx and Ry, is a cyclic peroxide with 4 to 8 chain links, which may comprise 1 or 2 additional oxygen atoms in the cyclic structure, and one or more substituents R3, identical or different, occupying any separate positions on the cycle, at least one representing a halogen atom, an -OH group, a -CF3 group, an aryl radical, an alkyl or alkoxy radical at CI to C5, an -NO2 group, the other substituent (s) having one of these correspondences or a hydrogen atom, with the possibility of substituting the carbonated peaks of the cyclic peroxide if applicable by one or more substituents as claimed for R3, with the possibility of two adjacent substituents forming a cyclic structure with 5 to 6 chain links, saturated or unsaturated, if applicable substituted by one or more substituents R3 in any position, with the possibility of the other substituent Rx or Ry being R3, and their addition salts with pharmacological acceptable acids. 2. Molecules as claimed in claim 1, wherein A represents a nitrous heterocycle selected from an aminoquinoline according to formula (II) or a 1,5-naphtyridine according to formula (III) below -R3 represents one or more identical or different substituents occupying separate positions, at least one representing a halogen atom, an -OH group, a -CF3 group, an aryl radical, an alkyl or alkoxy radical at C1 to C5, an -NO2 group, the other substituent (s) having one of these correspondences or a hydrogen atom, -R4 represents a linear, ramified or cyclic alkyl radical at CI to C5, or a hydrogen atom. 3. Molecules as claimed in claim 1, wherein A represents a radical according to formula (IV) R5 CHOH (IV) wherein R5 represents an aryl radical or a nitrous heterocyclic residue. 4. Molecules as claimed in claim 3, wherein R5 is a 9- phenanthrenyl or 4-quinoleinyl radical, possibly substituted by one or more R3 groups. 5. Molecules as claimed in claim 1, wherein A represents a phenol-2 (aminomethyl) residue according to formula (V) wherein R3, Ra and Rb are as claimed in claim 1. Molecules as claimed in claim 1, wherein A represents a biguanide residue selected from proguanil derivatives according to formula (VI) or cycloguanil according to formula (VII) wherein R3 is as claimed in claim 1. Molecules as claimed in claim 1, wherein A represents a residue of pyrrolidine and more particularly of pyrimethamine according to formula (VIII) wherein R3 is as claimed in claim 1 Molecules as claimed in claim 1, wherein A represents an acridine residue according to formula (X) (X) wherein R3 and R4 are as claimed in claims 1 and 2, respectively. 9. Molecules as claimed in any one of the preceding claims 1 to 8, wherein Rx and Ry form a cyclic peroxide together. 10. Molecules as claimed in claim 9, wherein Rx and Ry represent a trioxane substituted by one or more substituents R3. 11. Molecules as claimed in any one of the preceding claims 1 to 10, wherein R3 represents a single substituent, said substituent being a halogen atom selected from F, CI, Br, I or 2 substituents occupying separate positions, one representing a halogen atom selected from F, CI, Br, I, and the other an alcoxy group. 12. Molecules as claimed in any one of the preceding claims 1 to 11, wherein Z1 and Z2 represent a cyclohexyl or bi-cyclopentyl radical. 13. Method to prepare dual molecules as claimed in Claim 1, wherein A is an amino-quinoline and Rx and Ry form a trioxane, wherein a compound according to formula (XI) wherein R3 is as claimed above and "hal" represents a halogen atom, is reacted with a diamine derivative according to formula (XII) R4— NH—Yi—Ui (XII) where R4 and Yi are as claimed above and Ui represents an -NH2 group, producing a compound according to formula (XIII) : wherein R3, R4 and Yi are as claimed above, b) -irradiation in the presence of molecular oxygen and a photosensitising agent, of a derivative according to formulas (XIV) to (XVII) below followed by the reaction with a diketone, such as 1,4-cyclohexadione according to formula (XVIII) or cis-bicyclo(3.3.0]Octane-3,7-dione according to formula (XIX) producing trioxanes functionalised with a ketone, according to the general formula (XX) wherein Z1, Z2 and R3 are as claimed above, c) -coupling of the derivative according to formula (XIII) with the trioxane according to formula (XX), by reductive arnination, followed if applicable by a reaction with a pharmaceutically acceptable acid, to obtain the coupling product in salt form. 14. Pharmaceutical formulations intended for the treatment of malaria comprising an effective quantity of at least one coupling product as claimed in any of claims 1 to 12, associated with a pharmaceutically inert vehicle. 15. Pharmaceutical formulations as claimed in claim 14, which may be administered by the oral, rectal or injectable route. 16. Pharmaceutical formulations as claimed in claim 15, comprising 10 to 100 mg of active ingredient per dosage unit for oral administration. 17. Pharmaceutical formulations as claimed in claim 16, wherein, for oral administration, they are presented in the form of tablets, pills, capsules or drops. 18. Pharmaceutical formulations as claimed in claim 15, comprising 10 to 50 mg of active ingredient per dosage unit for administration by injection. 19. Pharmaceutical formulations as claimed in claim 15, for administration Py injection, they are presented in the form of solutions for injection by the intravenous, subcutaneous or intramuscular route, produced from sterile or sterilisable solutions, or suspensions or emulsions. Dated this 30 th day of September, 2002 [DIPAK MUNDRA] OF REMFRY & SAGAR ATTORNEY FOR THE APPLICANTS

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