Abstract:
The invention concerns pharmaceutical compositions with antimalaria and antibabesiosis activity, the active substances of these compositions and their use for formulating antimalaria drugs.

Description:
This application is a continuation of international application PCT/FR97/01336 filed Jul. 17, 1997, which designated the United States. 
    
    
     FIELD OF THE INVENTION 
     The invention concerns pharmaceutical compositions with antimalaria and antibabesiosis activity as well as the principal active substance of these compositions and their use in formulating antimalaria drugs. 
     BACKGROUND OF THE INVENTION 
     Malaria remains one of the most important parasitic diseases in the tropics. In endemic zones, malaria is an integral part of the environment and comprises one of the most powerful deterrents to the development of vast geographical areas. In such zones, all inhabitants are infected from birth to death, several times a year (up to 1,000 times in Congo), and only survive because of defense mechanisms acquired during the first years of life. It is during these early years, especially between the age of 6 months and 2 years, that malaria causes mortality, at a rate difficult to estimate. 
     Today, nearly two billion human beings live in endemic areas, often in highly unfavorable conditions, and are exposed to the risk of malaria, suffering its morbid or even fatal effects, often without health care. Protecting these risk groups, which account for more than one-third of the earth&#39;s population, is a major public health challenge. Several million cases of malaria are registered each year. Most, including the most severe often fatal forms of the disease, are caused by Plasmodium falciparum (80% of the cases worldwide). Developed countries are not spared: the number of imported cases increases steadily due to the progression of international transportation. 
     Drug-resistant Plasmodium falciparum is now the greatest threat to the fight against malaria. Resistance appeared in the early sixties in Thailand and in Columbia, then spread, reaching Africa in 1978. Movements in populations have also played a role in the development of resistance and chloroquine-resistant Plasmodium falciparum is now widespread throughout the world. Resistance to the second line sulfamide/pyrimethamine combination is already widespread in chloroquine-resistant areas of Southeast Asia and South America. The current emergence of multidrug resistant strains, unresponsive to any of the available antimalaria drugs, is a major threat. 
     Among the currently available methods used to fight against malaria, the fight against larvae and the reduction of the source remains to be analyzed in terms of reduced case incidence. These methods do not appear to have a decisive effect on malaria. Methods based on treating homes with insecticides have several inconveniences (resistance, poor acceptance by the population, high cost, no effect in the savannah environment) while personal protection using pyrethrinoid impregnated nets is known to be effective, but subject to many limitations. 
     A polyvalent vaccine, fully active against the different forms of the parasite and all the types of malaria, has constantly been postponed and now appears to be far off (Walsh J, Science 1987, 235, 1319, Butcher, Parisitologie, 1989, 98, 315). For many years to come, chemotherapy will remain the necessary method for populations living in endemic zones. 
     More than 250,000 compounds tested in a major research effort undertaken in 1963 at the Walter Reed Center in Washington D.C. led to market approval for mefloquine (Lariam®) in 1985. Resistance to this new antimalaria drug has however been induced experimentally and cases of resistance have been reported. Of even greater concern is the cross-resistance demonstrated between mefloquine and other amino-alcohols such as quinine or new drugs currently in the experimental phase such as halofantrine marketed in 1989 (Halfan®) (J. Rieckmann, Ann. Rev. Med. 1983, 34, 321-335; D. Warhust, Drugs, 1987; 33: 50-65; Struchler, Parasitol Today 1989, 5:39-40). 
     Babesia, which belong to a hematozoan class comparable with Plasmodium, are particularly important animal parasites. Babesia and Plasmodium are very similar, but Babesia usually causes animal disease, mainly infecting cattle and dogs. The principal causal species are Babesia bovis, Babesia cani, Babesia gibsoni, Babesia divergens, and Babesia gibemina. Babesia equi is specifically implicated in equine disease. 
     The inventors have evidenced a new class of compounds with strong antiprotozoal activity, particularly antimalaria and antibabesiosis activity. In addition, this antimalaria activity exhibits a novel mechanism and could thus avoid much feared drug resistance in this therapeutic class. The concept of these compounds was guided by the demonstration that phospholipid metabolism in the malaria-infected red cell is abundant and specific. Asexual parasite proliferation occurring within the erythrocyte (the parasite phase associated with clinical signs of the disease) is accompanied by substantial phospholipid (PL) neosynthesis required for the biogenesis of Plasmodium membranes. The intraerythrocyte phospholipid level increases after malarial infection, rising to 500% when the parasite has reached its mature state. 
     Consequently, there is an excess of phospholipid biosynthetic metabolism in the erythrocyte after Plasmodium infection. In host mammals, mature erythrocytes are totally devoid of PL biosynthesis. 
     The different biosynthesis pathways of phosphatidylethanolamines (PE) and phosphatidylcholine (PC) are schematically represented in FIG. 1. The present invention utilizes the observation that the parasite&#39;s development is blocked by substances interfering with this metabolism at doses quite below those interfering with healthy cells. Certain commercial quaternary ammoniums, with other known therapeutic activities or not, inhibit the development of Plasmodium falciparum but at doses incompatible with use as drugs because of side effects, notably on the cholinergic system. These quaternary salts are trimethylalkylammoniums long recognized for their effect on surface tension or their smooth muscle relaxing properties (see decamethonium, Procuran®) when given via parenteral administration. ISOMAA (Acta Pharmacol, Toxicol 45 (5) 1979 and Biochem. Pharmacol 28 (7) 975-980) studied the action of quaternary alkyltrimethylammoniums on erythrocyte membranes in the rat and noted a protective effect on the membrane at low concentrations and a hemolytic effect at higher doses. These long-chain quaternary trimethylammoniums appear to induce changes in cell surfaces at relatively high concentrations (ISOMAA Acta Pharmacol Toxicol. 44(1) 1979 36/42). The mechanism of action, modifying the plasma membrane double lipid layer, would involve a surface tension mechanism effective at relatively high concentrations. 
     The series of long straight chain bis trimethylalkylammoniums have been studied, notably for their depolarizing activities on diverse cell models (Kratskin I, Gen. Pharmacol. 1980, 11(1) 119-26 and Skylarov Dokl. Akad; Nauk SSSR 1988 303 (3) 760-3). The only therapeutic activities are cholinomimetic or cholinolytic effects noted by Danilov AF (Acta Physiol; Acta Sci. Hung 1974 45 (3-4) 271-80). It is noted that all these agents affecting surface tension carry trimethylammoniums on both ends of a hydrocarbon chain generally composed of 12 methylene moities. The nitrogen atom thus carries identical, relatively small, substituents on a carbon chain usually less than 12 atoms long. 
     SUMMARY OF THE INVENTION 
     The inventors have found that, in a surprising way, diminishing the symmetry around the nitrogen atom in the quaternary biammonium components, and more generally increasing their steric bulk, strongly inhibits the choline transporter in the parasite. This dyssymmetry around the nitrogen atom is particularly notable for the smaller substituents. Conjugated with an adjustment of the length of the hydrocarbon chain carrying these two bisammonium polar heads, this surprising discovery can be used to multiply the action against Plasmodium by a factor of 1000 or even 100,000 compared with known short-chain derivatives. The optimal length of the aliphatic chain separating the two quaternary ammonium moieties influences the antiplasmodium activity. The alteration of the choline transformation into phosphatidylcholine is specific to hematozoal parasites, notably Plasmodium falciparum at the active concentrations used. There is no change in the other biosynthetic systems. 
     The invention thus concerns new chemical molecules containing two quaternary ammonium groups on the ends of a hydrocarbon chain and exerting a strong antimalaria and antibabesiosis activity. Antimalaria and antibabesiosis activity is understood as the capacity to prevent the development of the parasite within the erythrocyte and or erythrocyte invasions, and to cause the death of the parasites initially present. It is remarkable that the compounds defined in this invention have the same antimalaria activity when tested on both chloroquine-sensitive and on multidrug-resistant strains. 
     Thus the invention concerns a pharmaceutical composition composed of a physiologically acceptable excipient and, as its active substance, a compound defined by the general formula (1): ##STR1## wherein R1 designates a hydrocarbon group with 1 to 20 carbon atoms, and 
     R2 and R3 are identical or different and independently designate a hydrocarbon group with 1 to 20 carbon atoms which may have methyl or ethyl substitution groups, or halogen substitution groups such as chlorine, bromine or iodine, or trifluoromethyl, trifluoroethyl or trifluoropropyl substitution groups, 
     where R1 is different from an ethyl group, R2 and R3 are not simultaneously methyl groups, 
     or 
     R1 designates a hydroxylalkyl group composed of 1 to 5 carbon atoms, where the hydroxyl groups may be etherified by a methyl, ethyl group substitution of the hydrogen atom or substituted with silicyl derivatives of the --Si(CH 3 ) 3  type, and 
     R2 and R3 are identical or different from each other and designate a saturated hydrocarbon which may be substituted with halogen groups such as chlorine, bromine or iodine, or with trifluoromethyl, trlfluoroethyl or trfluoropropyl groups, 
     or 
     R1 designates a mono-or polyunsaturated hydrocarbon with 1 to 6 carbon atoms, 
     and 
     R2 and R3 are identical or different and designate a straight- or branched-chain alkyl group composed of 1 to 20 hydrocarbon units which may have methyl or ethyl substitution groups, or halogen substitution groups such as chlorine, bromine or iodine, or trifluoromethyl, trifluoroethyl or trifluoropropyl substitution groups, 
     or 
     R1 designates a hydrocarbon with 1 to 20 carbon atoms, and 
     R2 and R3 form, together with nitrogen, a saturated heterogeneous cycle composed of 4 to 5 carbon atoms where one of the carbon atoms may be replaced by a silicium atom, an oxygen atom or a sulfur atom, this cycle also possibly carrrying an alkyl substitution with 1 to 3 carbon atoms which themselves may be hydroxylated, halogenated, or silicylated, 
     where R1&#39;, R2&#39; and R3&#39; have the same definition as R1, R2 and R3 in the formula (1), without the restriction concerning the methyl and ethyl groups, the two polar heads being identical or not; 
     and where X designates a hydrocarbon which may have an alkyl substitution with 1 to 3 carbon atoms, the hydrocarbon chain having 12 to 26 carbon atoms. 
     Preferentially, the two polar heads of the above-described components are identical. 
     More specifically, the pharmaceutical compositions of the invention include an active substance defined by the general formula (1), in which the substitutions are chosen in accordance with the following combinations: 
     R1 designates an alkyl group chosen among the following: methyl, methylethyl, propyl, butyl, sec-butyl, tert-butyl, pently, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, and 
     R2 and R3 are identical or different and independently designate an alkyl group chosen among the following: ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pently, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl which may carry methyl or ethyl substitution groups, or halogen substitution groups such as chlorine, bromine or iodine, or trifluoromethyl, trifluoroethyl or trifluoropropyl substitution groups, 
     or 
     R1 is a hydroxyalkyl group composed of 1 to 5 carbon atoms, namely hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypentyl groups, where these hydroxylated groups may be etherified by substitution of a methyl, ethyl, or --Si--(CH 3 ) 3  group for the hydrogen atom, and 
     R2 and R3 are identical or different from each other and can be a saturated propyl, isopropyl, butyl, sec-butyl, tert-butyl, pently, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl hydrocarbon which may carry halogen substitution groups such as chlorine, bromine or iodine, or trifluoromethyl, trifluoroethyl or trifluoropropyl substitution groups, 
     or 
     R1 designates a mono- or polyunsaturated hydrocarbon chain of the type propenyl, propynyl, butenyl, butynyl, butadienyl, pentenyl, pentadienyl, pentynyl, hexenyl, hexadienyl, hexynyl, isoprenyl, and 
     R2 and R3 are identical or different and designate a straight- or branched-chain alkyl composed of 1 to 20 hydrocarbon units such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptly, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl which may itself carry halogen substitution groups such as chlorine, bromine or iodine, or trifluoromethyl, trifluoroethyl or trifluoropropyl substitution groups, 
     or 
     R1 designates a methyl, methylethyl, propyl, butyl, sec-butyl, tert-butyl, pently, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl group, and 
     R2 and R3 form, together with nitrogen, a saturated heterogeneous cycle composed of 4 to 5 carbon atoms where one of the carbon atoms may be replaced by a silicium atom, an oxygen atom or a sulfur atom, this cycle also possibly carrrying a methyl, ethyl, hydroxymethyl, hydroxyethyl, methyl ethyl or hydroxypropyl substitution, or a trifluoromethyl or trifluoroethyl substitution, or a trimethylsilicyl or trimethylsilicyloxy substitution. 
     Preferentially, X is here a saturated hydrocarbon, preferably a straight 14 to 26 chain, and with preferably between 14 and 22, for example, 16 carbon atoms. 
     Avantageously, the active substance is chosen among the following compositions: 
     N,N&#39; dimethyl-N,N&#39;-diethyl-N,N&#39;-dipropyl-1,16-hexadecanediaminium, dibromide, 
     N,N&#39; dimethyl-N,N&#39;-diethyl-N,N&#39;-dipropyl-1,20-eicosanediaminium, dibromide, 
     N,N&#39; dimethyl-N,N,N&#39;,N&#39;-tetraethyl-1,16-hexadecanediaminium, dibromide, 
     N,N&#39; dimethyl-N,N,N&#39;,N&#39;-tetraethyl-1,18-octadecanediaminium, dibromide, 
     N,N&#39; dimethyl-N,N,N&#39;,N&#39;-tetraethyl-1,21-heneicosanediaminium, dibromide 
     -1,1&#39;-(1-14-tetradecanediyl) bis (1-methylpyrrolidinium) dibromide, 
     -1,1&#39;-(1-16-dexadecanediyl) bis (1-methylpyrrolidinium) dibromide, 
     -1,1&#39;-(1-16-hexadecanediyl) bis (2-hydroxymethyl-1-methylpyrrolidinium) dibromide, 
     N,N&#39;-di-(2-hydroxyethyl)-N,N,N&#39;,N&#39;-tetrapropyl-1,20-eicosanediaminium dibromide. 
     In case of a heterogeneous cycle with nitrogen, R1 can be a methyl, giving the following type of polar head: ##STR2## 
     1-1&#39;-1,16-hexadecanediyl bis (1-methylpyrrolidinium) dibromide, a compound carrying two of these polar heads, constitues a preferred example of the active substance of the invention. 
     The invention also concerns a compound used as a therapeutic agent, preferably as an antimalaria and/or antibabesiosis agent. 
     The invention also concerns the utilization of a compound defined by the general formula (1) to obtain an antimalaria drug, or an antibabesiosis drug: ##STR3## wherein: R1 designates a hydrocarbon group with 1 to 20 carbon atoms, and 
     R2 and R3 are identical or different and independently designate a hydrocarbon group with 1 to 20 carbon atoms which may have methyl or ethyl substitution groups, or halogen substitution groups such as chlorine, bromine or iodine, or trifluoromethyl, trifluoroethyl or trifluoropropyl substitution groups, 
     or 
     R1 designates a hydroxylalkyl group composed of 1 to 5 carbon atoms, where the hydroxyl groups may be etherified by a methyl, ethyl group substitution of the hydrogen atom or substituted with silicyl derivatives of the --Si(CH 3 ) 3  type, and 
     R2 and R3 are identical or different from each other and designate a saturated hydrocarbon which may be substituted with halogen groups such as chlorine, bromine or iodine, or with trifluoromethyl, trifluoroethyl or trifluoropropyl groups, 
     or 
     R1 designates a mono-or polyunsaturated hydrocarbon with 1 to 6 carbon atoms, and 
     R2 and R3 are identical or different and designate a straight- or branched-chain alkyl group composed of 1 to 20 hydrocarbon units which may have methyl or ethyl substitution groups, or halogen substitution groups such as chlorine, bromine or iodine, or trifluoromethyl, trifluoroethyl or trifluoropropyl substitution groups, 
     or 
     R1 designates a hydrocarbon with 1 to 20 carbon atoms, and 
     R2 and R3 form, together with nitrogen, a saturated heterogeneous cycle composed of 4 to 5 carbon atoms where one of the carbon atoms may be replaced by a silicium atom, an oxygen atom or a sulfur atom, this cycle also possibly carrrying an alkyl substitution with 1 to 3 carbon atoms which themselves may be hydroxylated, halogenated, or silicylated, 
     where R1&#39;, R2&#39; and R3&#39; have the same definition as R1, R2 and R3 in the formula (1), 
     and where X designates a saturated hydrocarbon containing --CH 2  -- groups or cyclic groups possibly carrying an alkyl substituion with 1 to 3 carbon atoms, this hydrocarbon chain having between 11 and 26 carbon atoms. 
     According to this aspect of the invention, use of compounds corresponding to the above defined active agents is more specifically preferred. 
     The invention also concerns a procedure for preparing a pharmaceutical composition characterized by an active substance such as that defined above by the general formula (1) being combined with a physiologically acceptable excipient. 
     In addition this active substance can be combined with a conventional additive, such as a preservative, an antioxidant or a dilution agent. 
     The invention also concerns the active substances of the invention, as defined by the general formula (1) relative to the pharmaceutical compositions. 
     The present invention also concerns a procedure for preparing the described compounds. The compounds designated by (1) may be prepared according to known techniques. These techniques Include the action of tertiary amine on an α-ω dihalogenated alkane giving either a dichloro, dibromo, or dilodo alkane. The reaction can take place without solvents, preferably under nitrogen atmosphere, whenever at least one of the reagents can serve as the solvent medium. The reaction can also be performed in a solvent chosen among alcohols, ketones, dimethylformamide, acetonitrile, ethers, polyglycol ethers, or a mixture of several solvents chosen among the preceding or their mixture in aromatic hydrocarbons such as toluene or benzene. The quaternary ammonium halide, for example dibromide if dibromoalkane is used, is thus isolated. 
     The proportions for the reagents are determined in accordance with the stoichiometry, but there can be an excess of the halogenated derivative, namely when the halogenated derivative can be used as the reaction solvent. 
     A salt of another mineral or organic acid can however be obtained by a usual procedure using an ion exchange resin. The reaction can be performed at room temperature, however the temperature will be raised to accelerate the process. This temperature will range between room temperature and the boiling temperature of solvent used. 
     If a non-symmetrical derivative is to be obtained, an equivalent tertiary amine is reacted with a primary ω-alkanol, then the alcohol group is halogenated using a hydrohalogenic acid, for example concentrated hydrobromic acid, giving an halogenated quaternary ammonium alkyl, which will then be reacted with the chosen second quaternary amine. 
     The final product can be isolated directly by crystallization from the reaction medium, it can also be separated form the solvent by evaporation and recrystallized in another solvent chosen among alcohols, ketones, esters, ethers, ether-alcohols, acetic acid. These compounds can be administered orally, parenterally, rectally, percutaneously or permucosally, in the form of tablets, enrobed tablets, capsules, solutions, syrups, emulsions, suspensions, or formulations enabling modulated release of the active substance. Such compositions can be administered to humans or animals at doses ranging from 0.01 mg/kg to 50 mg/kg. 
     For an antibabesiosis application, the pharmaceutical compositions are formulated in accordance with veterinary standards. 
     DETAILED DESCRIPTION OF THE INVENTION 
     Besides the preceding dispositions, the invention concerns other dispositions described in the following which refers to examples of implementation of the procedure which is the object of the present invention. These examples are given solely as illustrations of the object of the invention and cannot be considered to limit the invention in any way. All the derivatives have been submitted to elementary analysis, with, compared with the calculated values, a 0.3% maximal tolerance in the results obtained. The melting points were measured in a capillary tube and have not been corrected, the boiling points have not been corrected, the pressure being measured with a Pirani gauge. The infrared spectra were obtained with a Philipps PU 9714 device using NaCl slices for liquids and KBr pellets for the solids. The NMR spectra were recorded on a Brucker WP 200 device in deuterochloroform solution or on a DMSOd6 compared with the reference TMS. Unless specifically stated otherwise, the products were isolated as bromhydrates. 
    
    
     EXAMPLES 
     I/ Synthesis of Certain Active Molecules 
     Example 1 
     --N,N&#39;-dimethyl-N,N&#39;-diethyl-N,N&#39;-dipropyl-1,14 tetradecanediaminium, dibromide 
     200 ml ethanol, 35.6 g (0.1 mole) are added to -1,14 dibromotetradecane and 11.1 g N-ethyl-N-methyl-1 propanamine. The mixture is refluxed for 8 hours to complete reaction, followed by thin-layer chromatography on a silicium plate in a solvent system such as propanol/pyridine/acetic acid/water. The solution is then evaporated and the residue is recrystallized in a isopropanol/ethyl acetate mixture. The crystalline form of the derivative defined is obtained, M.P.=185/190° C. 
     The non-commercial α-ω dibromated derivatives can be synthesized by methods including malonic synthesis from a dibromoalkane derivative with four less carbon atoms. For example, as described below, synthesis (a/, b/, c/ and d/) of -1,14-dibromotetradecane from dibromodecane: 
     a/ Synthesis of the ethyl ester of -2,13-diethoxycarbonyl-1,14-tetradecanedionic acid 
     One atom/gram of sodium (23 g) is disolved in 500 ml anhydrous ethanol, 1.1 mole of diethyl malonate is then added. 0.5 moles of -1,10-dibromodecane are added to the resulting suspension at 30 to 50° C. The mixture is refluxed for several hours then, after distillation and water washings, the raw product is distilled. This gives the pure derivative defined in the title in the form of an oil distilling at 160/170° C. under 10 -3  mbar with a 80% yield. 
     b/ Synthesis of -1,1,4-tetradecanedicarboxylic acid 
     All of the product obtained in step a/ described above is saponified in a mixture of 170 g potassium and 200 ml water. The alcohol product is distilled followed by addition of concentrated sulfuric acid to strongly acidify the medium. The mixture is held at boiling until the end of the decarboxylation. When all the CO 2  has been removed, the mixture is cooled and extracted with a non-miscible solvent washed to neutrality. The derivative described in the title is obtained by evaporation and recrystallization, M.P.=160° C. 
     c/ Synthesis of -1,14-tetradecanediol 
     The product obtained in step b/ is esterified in the presence of excess ethanol and a few milliliters of sulfuric acid brought to boiling. The reaction process can be followed by C.C.M. in the following solvent system: formic acid/ethyl formate/toluene. After evaporaing the excess alcohol and washing with water in the presence of a non-miscible solvent, the ethyl ester of -1,14-tetradecanedioic acid is obtained in the form of a thick oil, boiling point=165° C. under 1 mbar. All of the product is reduced by LiAlH 4  in solution in the THF, the reduction is followed by C.C.M. After treating with dilute acid, the product is extracted with a solvent then chromatographed on a silicium column with a hexane/ethyl acetate mixture. Total yield from the diacid is greater than 65%. 
     d/ Synthesis of -1,14-dibromotetradecane 
     23 g (0.1 mole) of dialcohol are added to 200 ml 48% bromhydric acid and refluxed for 24 hours. After cooling, the organic phase is separated, redissolved in chloroform, and washed with water. The derivative defined in the title is obtained by chromatography on a silicium column with hexane with a 45% yield from the alcohol, the melting point of this product is 43° C. 
     The following derivatives are obtained by proceeding as described in example 1, using the corresponding dibromoalkanes instead of-1,14-dibromotetradecane: 
     Example 2 
     --N,N&#39;-dimethyl-N,N&#39;-diethyl-N,N&#39;-dipropyl-1,15-pentadecanediaminium dibromide, M.P.=230° C. 
     Example 3 
     N,N&#39;-dimethyl-N,N&#39;-diethyl-N,N&#39;-dipropyl-1,16-hexadecanediaminium dibromide, M.P.=232° C. 
     Example 4 
     N,N&#39;-dimethyl-N,N&#39;-diethyl-N,N&#39;-dipropyl-1,17-heptadecanediaminium dibromide, M.P.=205° C. 
     Example 5 
     N,N&#39;-dimethyl-N,N&#39;-diethyl-N,N&#39;-dipropyl-1,18-octadecanediaminium dibromide, M.P.=175° C. 
     Example 6 
     N,N&#39;-dimethyl-N,N&#39;-diethyl-N,N&#39;-dipropyl-1,20-eicosanediaminium dibromide, M.P.=130° C. 
     Example 7 
     N,N&#39;-dimethyl-N,N&#39;-diethyl-N N&#39;-dipropyl-1,22-cosanediaminium dibromide, M.P.=130° C. 
     Example 8 
     N,N,N,N&#39;,N&#39;,N&#39;-hexapropyl-1,14-tetradecanediaminium dibromide 
     3.56 g (10 mM) of -1,14-dibromotetradecane are added to 20 ml tripropylamine and held at 80/90° C. over night. The excess tertiary amine is evaporated under vacuum, and a minimal amount of ethanol is added to redissolve the derivative which is reprecipitated with ether. The derivative defined in the title is obtained by recrystallization in a isopropanol/iisopropylic ether mixture, M.P.=170° C. 
     Example 9 
     N,N,N,N&#39;,N&#39;,N&#39;-hexapropyl-1,16-hexadecanediaminium dibromide. 
     The hygroscopic form of the derivative defined in the title is obtained by applying the same procedue as described above using -1,16-dibromohexadecane and recrystallizing with methanol/ether, M.P.=185° C. 
     Example 10 
     N,N,N,N&#39;, N&#39;,N&#39;-hexapropyl-1,20-eicosanediaminium dibromide 
     The malonic synthesis described in example 1 is applied to -1-16-dibromohexadecane to obtain pure -1,20-eicosandiol after column chromatography, M.P.=93° C. Bromation following the prodecure described in example 1-d/-variant 2, produces -1,20-dibromoeicosane, M.P.=62° C. Reaction with tripropylamine according to the procedure described in example 1 produces the crystalline form of the derivative defined in the title, M.P.=205° C. 
     Example 11 
     N,N,N,N&#39;,N&#39;,N&#39;-hexapropyl-1,24-tetracosanediaminium dibromide 
     In this example, the malonic synthesis uses the bromated derivative described above and produces -1,24-dibromotetracosane, which, when treated with tripropylamine as described in example 1 gives the derivative described in the title, M.P.=105° C. 
     Example 12 
     N,N,N,N&#39;,N&#39;,N&#39;-hexapropyl-1,16-hexadecanediaminium dibromide 
     The crystalline form of the derivative defined in the title is obtained using the -1,16-dibromohexadecane derivative and tripropylamine according to the conditions described above, M.P. 227° C. 
     Example 13 
     N,N&#39;-dimethyl-,N,N,N&#39;,N&#39;-tetraethyl-1,16-hexadecanediaminium dibromide 
     The derivative defined in the title is obtained by replacing tripropylamine with N-methyldiethylamine, M.P.=170° C. 
     Example 14 
     N,N&#39;-dimethyl-,N,N,N&#39;,N&#39;-tetraethyl-1,18-octadecanediaminium dibromide 
     Operating as described above with -1,18-dibromooctadecane gives the derivative defined in the title, M.P.=206° C. 
     Example 15 
     N,N&#39;-dimethyl-,N,N,N&#39;,N&#39;-tetraethyl-1,21-heneicosanediaminium dibromide 
     Using the corresponding diol obtained according to the method described by Lukes (Col. Czech. Chem. Comm. 26, -1961- 1719/1722) and by action of phosphorus tribromide according to example 1 gives the α-ω dibromated derivative which is reacted with N-methyldiethylamine to produce the derivative defined in the title, M.P.=205° C. 
     Example 16 
     -1,1&#39;-(1,14-tetradecanediyl)bis(1-methylpyrrolidium) dibromide 
     21.36 g (0.06 mole) of -1,14-dibromodecane and 11.07 g (0.13 mole) N-methylpyrrolidine are added to 200 ml ethanol, refluxed for 6 hours until complete reaction. The derivative defined in the title is obtained after evaporation to dry and recrystallization in an ethanol/ether mixture, M.P.=192° C. 
     Example 17 
     -1,1&#39;-(1,16-hexadecanediyl)bis(1-methylpyrrolidium) dibromide 
     With the conditions of the example given above and with -1,16-dibromodecane, using N-methylpyrrolidine gives the cristalline form of the derivative defined in the title, M.P.=178° C. 
     Example 18 
     -1,1&#39;-(1,14-tetradecanediyl)bis(2-hydroxymethl-1 -methylpyrrolidium) dibromide 
     If 2-hydroxymethyl-1-methyl-pyrrolidine is substituted for N-methylpyrrolidine in the preceeding example, the derivative defined in the title is obtained, M.P.=95° C. 
     Example 19 
     -1,1&#39;-(1,22-docosanediyl)bis(2-hydroxymethl-1 -methylpyrrolidium) dibromide 
     With 1,22-dibromodocosane, starting with the corresponding dialcohol, iteslf synthesized by the action of bromhydric acid on the docosa-1,21-diene, the derivative defined in the title is obtained, M.P.=102° C. 
     Example 20 
     -1,1&#39;-(1,16-hexadecanediyl)bis(1-methyl-3-hydroxymethylpyrrolidium) dibromide 
     With the conditions given in example 16 and with -1,16-dibromohexadecane and 1-methyl-3-piperidinemethanol, the derivative defined in the title is obtained, M.P.=107° C. 
     Example 21 
     -1,1&#39;-(1,16-hexadecanediyl)bis(1-methylmorphofinium) dibromide 
     Using the same bromate derivative and N-methylmorpholine, the derivative defined in the title is obtained, M.P.=85° C. 
     Example 22 
     N,N&#39;-didodecyl-N,N,N&#39;,N&#39;-tetramethyl-1,16-hexadecanediaminium dibromide 
     With N-dimethyllaurylamine using the dibromated derivative given above, the derivative defined in the title is a white product, M.P.=128° C. 
     Example 23 
     N,N&#39;-didodecyl-N,N,N&#39;,N&#39;-tetramethyl-1,16-octadecanediaminium dibromide 
     As above with the C18 dibromo derivative, the derivative defined in the title is obtained, M.P.=103° C. 
     Example 24 
     N,N&#39;-di(2-propynyl)-N,N,N&#39;,N&#39;-tetramethyl-1,14-tetradecandiaminium dibromide 
     Using N-dimethylpropagylamine under the preceding conditions gives the derivative defined in the title, M.P.=145° C.; the NMR spectrum recorded with the DMSOd6 shows characteristic chemical shifts: 3.4 ppm (m), 4H, --N--CH2--CH2--, 4.1 ppm; 4.1 ppm (t), 2H CH+C--; 4.5 ppm (d) 4H, C--CH2--N-- 
     Example 25 
     N,N&#39;-di(2-propenyl)-N,N,N&#39;,N&#39;-tetramethyl-1,14-tetradecanediaminium dibromide 
     As above, with N-dimethylallylamine, the derivative defined in the title is obtained, M.P.=50/60° C. The characteristic NMR chemical shifts are -4.0 ppm (d), 4H, CH--CH2--N-5.6 ppm (m) 4H, CH2═CH--; 6.0 ppm (m), CH2═CH--CH2. 
     Example 26 
     N,N&#39;-di(3-butynyl)-N,N,N&#39;,N&#39;-tetramethyl-1,14-tetradecanediaminium dibromide 
     Likewise as above, with the corresponding acetylinic amine, the derivative defined in the title is obtained, M.P.=170° C. The NMR spectrum has the following chemical shifts: 2.75 ppm (td), 4H, CH2+C--C--CH2--CH2--N, 3.1 ppm (t) 2H, CH+C--CH2; 3.25 ppm (m) 4H, CH+C--CH2--CH2--N--. 
     Example 27 
     N,N&#39;-di(2-hydroxyethyl)-N,N,N&#39;,N&#39;-tetrapropyl-1,14-tetradecanediaminium dibromide 
     With N-dipropylethanolamine and the C14 bromide derivative, the derivative defined in the title is obtained, M.P.=188/190° C. 
     Example 28 
     N,N&#39;-di(2-ethoxyethyl)-N,N,N&#39;,N&#39;-tetrapropyl-1,14-tetradecanediaminium dibromide 
     Likewise as above, with N-dipropyl-2-ethoxyethylamine, the derivative defined in the title is obtained, M.P.=145/150° C. 
     Example 29 
     N,N&#39;-di-(2- hydroxyethyl)-N,N,N&#39;,N&#39;-tetrapropyl-1,16 hexadecane diaminium dibromide 
     As in example 27, with the -1,16-dibromohexadecane instead of -1,14-tetradecane and the title compound is obtained, M.P.=120° C. 
     Example 30 
     N,N&#39;-di(2-hydroxyethyl)-N,N,N&#39;,N&#39;-tetrapropyl-1,20-eicosanediaminium dibromide. 
     By action of the C20 dibromide derivative, as in the preceding example, the derivative defined in the title is obtained, M.P.=85/90° C. 
     II/ Antimalaria Activity 
     The antimalaria activity of the derivatives presented in the preceding examples has been tested in humans infested with Plasmodium falciparum. The product to test was placed in contact with infected human erythrocytes for 24 hours. A radioactive nucleic acid precursor, ( 3  H) hypoxanthine was then added. The precursor is only incorporated into cells infected with growing parasites, that is in cells which the drug will not have affected. 
     The capacity to incorporate a precursor or not reflects the viability of the infested cells. The test duration is 60 to 70 hours (DESJARDINS R.E., CANFIELD C. J., HATNES J. D, and CHULAY J. D., Antimicrob. Agents Chemother. 1979, 16, p 710-718). In Table 1, below, the results are expressed as ED50, i.e. the product dose in the experimental medium which inhibits parasite growth in vitro by 50%. 
     The mechanism of action was verified on the different derivatives defined in the invention by studying the specific interference with the biosynthesis of different biomolecules, nucleic acids, proteins and phospholipids using the incorporation of the radiolabeled precursors ( 3  H)hypoxanthine, ( 3  H) isoleucine, (3H) choline. Specificity phospholipid metabolism was determined by comparison of the effect on ( 3  H) ethanolamine incorporation into phosphatidylethanolamine (Ancelin M. L., Vialettes F. and Vial H. H. 1991, Anal. Biochem. 199, 203-209. 
     Antimalaria Activity of G25 in the Monkey Infected by Human P. falciparum Parasites 
     Besides chimpanzees, only two South American monkey species, Aotus and Saimiri seirius, can be infected by P. falciparum. Currently, infection of Aotus monkeys with the human parasite is the best, and quasi-unique, model for evaluating therapeutic or vaccinal interventions against malaria (Collins W. E., Gallaud C. G., Sullivan J. S., and Morris C. L., &#34;Selections of different strains of Plasmodium falciparum for testing blood stages in Aotus nancymal monkeys&#34; An. J. Trop. Med. Hyg., 1994, 51 (2) 224-232). 
     The antimalaria activity was thus evaluated in the Aotus lemurinus monkey infected by the FVO (falciparum Vietnam Oaknoll) isolate of P. falciparum. This isolate is chloroquine-resistant and inevitably lethal for Aotus monkeys at the &#34;Fundacion Centro de Primates&#34; at the University del Valle, Cali, Colombia. 
     As shown in Figure 6, the Aotus monkey was infected by P. Falciparum (FVO isolate) on day 0. Treatment with G25 (dissolved in 0.9% NaCl) was initiated when the parasitemia reached 5.6%; 16 doses (0.2 mg/kg b.i.d. for 8 days) were given. The decline in parasitemia was evident at the second dose. The parasitemia in a monkey treated by combination sulfadoxine/pyrimethamine (FANSIDAR) is given for comparison. 
     In all, 15 monkeys were infected, then treated with G25 given by intramuscular injections at doses ranging from 0.010 to 0.2 mg/kg. Complete cure (validated by PCR) was achieved with no recurrences (the monkeys were followed for 6 months and checked for susceptibility to a new infection) for the doses as low as 0.030 mg/kg. Given at the dose of 0.01 mg/kg, G25 was active (parasite clearance) but did not lead to complete cure (recurrence observed). 
     Considering that the maximal tolerable dose in the monkey is approximately 1.5 mg/kg, it follows that the therapeutic index (LD 50  /ED 50 ) in the monkey is above 50. 
     III/ Antimalaria Activity and Toxicity 
     In order to evaluate the therapeutic index of the different products, the activity of these products was tested in vivo and compared with acute toxicity in animals. This activity was measured using the test described by PETERS W. (Chemotherapy and Drug resistance in Malaria, 1970). A compound was administered for four consecutive days to mice previously infected with Plasmodium vinckei, petterei or chabaudi. The said compound was dissolved in a 0.9% NaCl solution. The preparations were thus administered intraperitoneally or subcutaneously in male Swiss mice infected by intravenous injection of Plasmodium petterei or Plasmodium chadaudi (10 6  infected cells). The compound was administered twice a day for four consecutive days, the first injection being performed two hours after the infestation and the second, 10 hours later. The parasitemia was determined on blood smears the day after the end of treatment. Toxicity was measured in vivo following the same schedule, the animals having received, under the same administration conditions as above, two injections per day for four days (semi-chronic toxicity). The results are expressed in lethal dose 50 (LD 50 ), i.e. the dose causing death in 50% of the animals. 
     The results of these trials are summarized in Table I, below, and expressed as therapeutic index, or the ratio of activity over toxicity measured under the identical conditions described above. 
     IV/ Specific Action 
     1- The molecules of this invention have a specific action on phospholipid metabolism as compared with nucleic acid metabolism, and within phospholipid metabolism. The in vitro activity tests were performed on human erythrocytes infested with Plasmodium falciparum. The radiolabeled precursors used, such as choline, ethanolamine or hypoxanthine, were added and enabled measurements of the effect of the product on these different metabolisms. All the compounds tested showed a specific action on the biosynthesis of phosphatidylcholine, with a tight correlation between action on this metabolism and the antimalaria action per se. 
     2- Inversely, the molecules of this invention have demonstrated a total absence of any action on other cellular systems. Thus their effects on the viability of the SAR lymphoblastoid cell line were measured: there is no correlation between the dose causing a 50% inhibition in the cell line viability LV50 and the effective dose ED50 against Plasmodium falciparum. This same ED50 was compared with the ED50 required to inhibit uptake of choline in central nervous system synaptosomes according to the method described by Tamaru (Brain Res. 473, 205-226). The effect on the nervous system is only observed for doses up to 100 to 1000 times higher. 
     V/ In vitro Antibabesia Activity 
     The screening process for antimalaria activity, based on parasite incorporation of ( 3  H) hypoxanthine was used to test the antimetabolic activity of such components against Babesia bovis, Babesia canis. A tight relationship was found between the rate of ( 3  H) hypoxanthine incorporation using standard measurements and the percentage of parasitized cells determined by microscopy. This metabolic activity was quantified and scored +++ in the table given below for molecules with a test showing a 50% inhibition of ( 3  H) hypoxanthine incorporation (ED50), these molecules having a concentration less than or equal to 0.01 micromoles. The score was ++ for the same activity at a concentration of 0.01 to 0.1 micromoles and finally + for a concentration under or equal to 1 micromole. 
     
                       TABLE I______________________________________    ED50 expressed in                 Therapeutic                           Antibabesia activityCompound micromoles   index     at 10 millimoles______________________________________EXAMPLE 1    0.01         50        ++EXAMPLE 2    0.01         42        +EXAMPLE 3    0.003        15        22EXAMPLE 4    0.002        17        ++EXAMPLE 5    0.001        12        +++EXAMPLE 6    0.003        15        ++EXAMPLE 7    0.01         35        ++EXAMPLE 8    0.1          20        +EXAMPLE 9    0.007        36        +++EXAMPLE 10    0.7          14        +EXAMPLE 11    1.6          28        +EXAMPLE 12    0.001        11        ++EXAMPLE 13    0.0005        6        +++EXAMPLE 14    0.00004      14        +++EXAMPLE 15    0.000003     12        +++EXAMPLE 16    0.0009        8        +++EXAMPLE 17    0.0006        7        +++EXAMPLE 18    0.001        22        +++EXAMPLE 19    0.07         40        +EXAMPLE 20    0.0003       17        +++EXAMPLE 21    0.001        25        +++EXAMPLE 22    1            20        ++EXAMPLE 23    0.1          35        +EXAMPLE 24    0.007        12        ++EXAMPLE 25    0.005        15        +++EXAMPLE 26    0.04         45        ++EXAMPLE 27    0.01         15        ++EXAMPLE 28    0.01         40        +++EXAMPLE 29    0,005        12        ++EXAMPLE 30    0,0003       55        +++______________________________________ 
    
     Figure Legends 
     Figure 1: Schematic representation of the different biosynthesis pathways of phosphatidylethanolamine (PE) and phosphatidylcholine (PC), 
     Figure 2: Correlation between antimalaria activity (ED50) and action on phospholipid metabolism (PL50) (R=0.86, which corresponds to a risk much less than 0.01%). LV50 denotes a 50% inhibition of cell viability. 
     Figure 3: Synthesis pathways of quaternary bisammoniums (fonction de &#34;n&#34;) 
     Figure 4: Reactions involving malonic syntheses. 
     Figure 5: Synthesis of bisammonium derivatives with acetylenic and ethylenic groups. 
     Figure 6: Antimalaria effect of G25 in the monkey infected with P. falciparum with a 6% parasitemia.