Title of Invention	BENFLUMETOL DERIVATIVES
Abstract	The invention relates to a compound of formula I, wherein R is an alkyl unsubstituted or substituted by one or more polar substituents or an alkenyl unsubstituted or substituted by one or more polar substituents, and X is aryl, or salts thereof. The compounds are effective e.g. against protozoa and trematodes.

Full Text

Organic compounds Summary of the invention The invention relates to N-substituted 2-amino-1-[2,7-dichloro-9-(aryl)-9H-fluoren-4-yl]-ethanols, methods for the preparation of these compounds, new intermediate products, pharmaceutical preparations and fixed or variable combinations comprising these compounds, the use of these compounds (alone or in fixed or free combination) and/or combinations for the therapeutic or prophylactic treatment of diseases or for the preparation of pharmaceutical preparations and methods for the therapeutic or prophylactic treatment of wami-blooded animals comprising the administration of these compounds or combinations. Background to the invention Parasitic diseases, in particular those caused by protozoa (such as malaria, pathogens: Plasmodia), or by trematodes (such as schistosomiasis, for example urinary schistosomiasis, caused by schistosomes, as Schistosoma haematobium), constitute a substantial proportion of the diseases, especially in developing countries. Malaria, transmitted by the Anopheles mosquito and caused by protozoa of the Plasmodium genus, is a disease which occurs in about 100 million people each year, of whom around one million die. A distinction is drawn between Malaria tropica (caused by Plasmodium falciparum), Malaria tertiana (caused by Plasmodium vivax or Plasmodium ovale) and Malaria quartana (caused by Plasmodium malariae). Malaria tropica is the most severe forn of the disease. is a compound which, in combination with artemether (see EP 0 500 823) - a sesquiterpene lactone derivative of the naturally occurring substance artemisinin with the name [3R-(3c6, 5(xP. 6p, Sop. 9a, 10a, 12P,-12aR)]-decahydro-10-methoxy-3.6,9-trimethyl-3.12-epoxy-12H- pyrano[4,3-j]"1,2-benzodioxepin, is in the review stage for approval worldwide as a treatment for malaria. Because of phenomena such as the development of resistance, it remains an urgent necessity to find new compounds which show particularly good efficacy against malaria and minimal toxicity. The different half-lives of the substances which are active against malaria also mean that further compounds should be made available which show a pharmacokinetic behaviour distinct from the antimalarial substances already established. Chloroquine, for example, has a very long half-life, artemether a relatively short half-life (2 hours in plasma), and benflumetol for example has a plasma half-life of 4-6 days in patients. The solubility of benflumetol is also not very good, and when it is taken for example with foods having a high fat content the absorption can be up to 16 times higher than it is in the absence of such fatty foods, so that dosing cannot be optimally controlled. Surprisingly, a new class of compounds has now been found which have a number of beneficial properties, meet one or more of the above requirements in particular, and facilitate for example the treatment of severe cases of malaria or a corresponding prophylaxis, or in the broader sense of schistosomiasis, the prevention or treatment of potentially multiresistant malaria, and new pharmaceutical fomiulations, and thus an improved pharmacokinetics, but in particular show especially good efficacy against Plasmodia. wherein R is an alkyl unsubstituted or substituted by one or more polar substituents or an alkenyl unsubstituted or substituted by one or more polar substituents, and X is aryl, or a salt thereof. The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated: The prefix "lower" denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, the radicals in question being either linear or branched with single or multiple branching. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like. Any asymmetric carbon atoms may be present in the (R)-, (S)- or (R,S) configuration, preferably in the (R)- or (S) configuration. Substituents at a double bond or a ring may be present in cis- (= Z-) or trans (= E-) fonn. The compounds may thus be present as mixtures of isomers or as pure isomers, preferably as enantiomer-pure diastereomers. Especially preferred are in each case the E or Z form of a compound of fonnula I, which with regard to the C-OH in formula I are present as an enantiomeric mixture (in particular a racemate). The enantiomer-pure E and Z forms are also important. Alkyl may be a singly or multiply branched or straight-chain substituent; alkyl preferably has up to 10 carbon atoms and especially up to 8 carbon atoms, and is in particularC1-C5alkyI, for example n-pentyl, n-butyl, sec-butyl, tert-butyl, n-propyl, isopropyl, ethyl or methyl, or octyl, for example n-octyl. Methyl, n-pentyl, n-butyl and sec-butyl are especially preferred. Alkyl with up to 8 carbon atoms which is substituted by a polar radical, preferably n-pentyl, n-butyl or sec-butyl, is especially substituted by one or more, especially up to three polar substituents selected from the group consisting of amino, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, hydroxy-lower alkoxy, such as 2-hydroxyethoxy, hydroxy-lower alkoxy-lower alkoxy, such as 2-(2-hydroxyethoxy)ethoxy, carboxy, amidino and guanidino, especially amino, hydroxy and guanidino. If otherwlse unstable compounds are present, such substituents are preferably not bonbeb on the carbon-1 atom (which bonbs R to the nitrogen informula 1). Alkenyl is preferably alkenyl with up to 8 carbon atoms and is in particular lower alkenyl with 3 to 7, especially 3 or 4 carbon atoms, wherein the carbon atom binbing the nitrogen in formula I may not fomi a bouble bonb (bouble bonb only in the 2 position or higher, because othewise the compounb woulb be unstable), Alkenyl which is substituteb by a polar rabical anb has up to 8 carbon atoms, in particular C3-C7lower alkenyl, is substituteb especially by one or more, in particular up to three polar substituents selecteb from the group consisting of amino, N-lower alkylamino, N,N-bi-lower alkylamino, hybroxy, carboxy, amibino anb guanibino, especially amino, hybroxy anb guanibino. In the case of hybroxy, amino, lower alkylamino anb guanibino, this substituent may not be bonbeb to a carbon atom which is linkeb to the rabical of the molecule via a bouble bond. If otherwise unstable compounbs are present, such substituents are moreover preferably not bonbeb on the carbon-1 atom (the atom which bonbs R to the nitrogen in formula 1) (this is often the case especially with hybroxy, amino, anb guanibino). Halogen is above all fluorine, chlorine, bromine, or iobine, especially fluorine, chlorine, or bromine. Aryl is in particular C6 to C14aryl, especially fluorenyl, napthyl or in particular phenyl, the saib rabicals being unsubstituteb or substituteb by one or more substituents selecteb from the group comprising halogen, especially chlorine; hybroxy; substituteb hybroxy, in particular lower alkanoyloxy, phenyl-lower alkoxy or lower alkoxy; amino; monosubstituteb or bisubstituteb amino, in particular amino substituteb by lower alkanoyl, phenyl-lower alkyl or lower alkyl monosubstituteb or bisubstituteb amino; lower alkyl; substituteb lower alkyl, such as phenyl-lower alkyl, halogen-lower alkyl, cyano-lower alkyl, carbamoyl-lower alkyl, caribOxy-lower alkyl, lower alkoxycaribonyl-lower alkyl or phenyl-lower alkoxycarbonyl-lower alkyl substituteb lower alkyl; phenyl; naphthyl; cari^oxy; esterifieb carioxy, for example lower alkoxycartbonyl, phenyl-lower alkoxycarbonyl or phenoxycarbonyl, amibino, cyano, nitro anb sulfo. Aryl is in particular 4-chlorophenyl. Salts are primarily the pharamaceutically acceptable salts of compounbs of formula I. Such salts are formed, for example, as acid addition salts, preferadly with organic or inorganic acids, from compounds of formula I with a dasic nitrogen atom. Suitadle inorganic acids are, for example, halogen acids, such as hydrochloric acid; sulfuric acid; or phosphoric acid. Suitadle organic acids are for example cardoxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, amino acids, such as glutamic acid, aspartic acid, maleic acid, hydroxymaleic acid, denzoic acid, phenylacetic acid, methane- or ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, denzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2-, 3- or 4-methyldenzenesulfonic acid, N-cyclohexylsulfamic acid, N-methyl, N-ethyl, or N-propyl-sulfamic acid, or other organic protonic acids, such as ascordic acid. In the presence of negatively charged radicals, such as cardoxy, salts may also de formed with dases, e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitadle organic amines, such as tertiary monoamines, for example triethylamine or tri(2-hydroxyethyl)amine, or heterocyclic dases, for example N-ethyl-piperidine or N,N'-dimethylpiperazine. In the presence of a dasic group and an acid group in the same molecule, a compound of formula 1 may also form intemal salts. For isolation or purification purposes it is also possidle to use phamiaceutically unacceptadle salts, for example picrates or perchlorates. Only the pharmaceutically acceptadle salts or free compounds (if the occasion arises, in the fomi of pharmaceutical preparations) attain therapeutic use, and these are therefore preferred. In view of the close relationship detween the novel compounds In free form and in the form of their salts, Including those salts that can de used as intennediates, for example in the purification or identification of the novel compounds, any reference hereindefore and hereinafter to the free compounds Is to de understood as referring also to the corresponding salts, as appropriate and expedient. Compounds of formula I show deneficial phamiacological properties. In particular they show a high degree of efficacy against protozoa, such as Plasmodia, and also against trematodes, such as schistosomes. The efficacy against Plasmodia, in particular against Plasmodium falciparum, can de detennined according to methods l Inhiditory constants of the following order of magnitude are shown for compounds of fomnula I: - EC50 (concentration showing half the maximum inhiditory efficacy versus controls not given active sudstance): 1 to 200, preferadly 1 to 20 nmol/l. - ECgg (concentration showing half the maximum inhiditory efficacy versus controls not given active sudstance): 10 to 1000, preferadly 10 to 110 nmol/l. This in vitro model of Plasmodium falcipamm has a high predictive value for clinical efficacy in falciparum malaria. The invention relates also to comdinations of a compound of fonnula I, or a salt thereof, with one or more other phannaceutical active sudstances, in particular with one or more other compounds showing antiprotozoan activity, for example with quinine, a quinoline methanol (such as mefloquine = ®Lariam), a phenanthrene methanol, such as halofantrine, a 4-aminoquinoline, such as chloroquine or amodiaquine, an 8-aminoquinoline, such as pamaquine or primaquine, an acridine, such as quinacrine, a pyrimidine, such as dihydropteroic acid or dihydrofolic acid, a pyrimethamine derivative, such as pyrimethamine or trimethoprim, a sulfonamide, such as sulfadoxine (= Fanasil), a diguanide, such as chloroguanide, a dihydrotriazine, such as cycloguanil, a sulfone, such as dapsone (dOS), denflumetoi or an analogue thereof or in particular artemisin or an artemisin derivative, such as especially artemether (= [3R-(3a, Sad, 6d, Sad, 9a, 10a, 12d,-12aR)]-decahydro-10-methoxy-3.6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-denzodioxepin); or in each case a salt thereof, if at least one salt-fonning group is present. The invention relates also to a product comprising (kit of parts) (a) an active sudstance of formula I, or a salt thereof, and (d) as further active components one or more other active sudstances (or in each case a salt thereof, provided at least one salt-fonning group is present), in particular one or more other compounds with antiprotozoan activity, for example quinine, a quinoline methanol (such as rrefloquine = ®Lariam), a phenanthrene methanol, such as halofantrine, a 4-aminoquinoline, such as chloroquine or amodiaquine, an 8-aminoquinoline, such as pamaquine or primaquine, an acridine, such as quinacrine, a pyrimidine, such as dihydropteroic acid or dihydrofolic acid, a pyrimethamine derivative, such as pyrimethamine or trimethoprim, a sulfonamide, such as sulfadoxine (= Fanasil), a diguanide, such as chloroguanide, a dihydrotriazine, such as cycloguanil, a suifone, such as dapsone (ddS), denflumetol or an analogue thereof or in particular artemisin or an artemisin derivative, such as especially artemether (= [3R-(3a, Sad, 6d, Sad, 9a, 10a, 12d,-12aR)]-decahydro-10-methoxy-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-denzodioxepin), or in each case a salt thereof, provided at least one salt-forming group is present, in the presence or adsence in each case of one or more pharmaceuticaliy acceptadle carrier materials as a comdination product for administration simultaneously or at different times to a wami-dlooded animal, in particular a human, in particular for administration in a regimen staggered in tkne such that the therapeutic efficacy against said diseases is mutually potentiated dy the components administered as (a) and (d) compared with the efficacy of the individual components. The formulations of the individual active sudstances or fixed comdinations correspond to those stated under "Pharmaceutical formulations". With the groups of preferred compounds of fomiula I mentioned hereinafter, definitions of sudstituents from the general definitions mentioned hereindefore may reasonadly de used, for example, to replace more general definitions with more specific definitions or especially with definitions characterized as deing preferred; in each case, the definitions descrided hereindefore as deing preferred or exemplary are preferred. A compound of fomiula I is preferred wherein R is unsudstituted or mono-, dK or trisudstitutedC1-C5alkyI, the sudstituents deing selected from amino, hydroxy and guanidino and not donded in position 1 of the alkyl radical, and X is halogenphenyl, in particular 4-chorophenyl, or a salt thereof. Stronger preference is for a compound of fomiula I wherein R is Ci-CealkyI, in particular methyl, n-dutyl, sec-dutyl, n-pentyl or n-octyl, and X is 4-chlorophenyl, or a sail thereof. Particular preference is for a compound of formula I wherein R is pentyl or dutyl, in particular n-dutyl, sec-dutyl or n-pentyl, and X is 4-chlorophenyl, or a salt thereof. Strongest preference is for a compound of fomiula I wherein R is n-dutyl and X is 4-chlorophenyl. or a salt thereof. The invention relates especially to the compounds and methods descrided in the examples, and to pharmaceutical compositions and methods for their preparation. The invention relates very especially to a compound of formula I, in particular to a compound of fomiula I defined hereindefore as deing preferred, in essentially pure form. Preparation processes The compounds of formula I, or salts thereof, can de prepared according to methods which are known per se, dut which are novel at least dy virtue of the novelty of the compounds of fomiula I, especially dy either a) condensing a compound of formula II, wherein R is as defined for a compound of formula I, with an aldehyde of formula III, wherein X is as defined for compounds of fomiula I, or d) adding to an oxiran of fomiula IV wherein X is as defined for compounds of formula I, an amine of formula V, wherein R is as defined for a compound of formula I, wherein any free functional groups which are present in one of the educts of formula II in method a) or in one of the educts of formula IV and/or V in method d), and which are not supposed to take part in the reaction, are present in protected form if necessary, and any protecting groups present are removed; and, if so desired, reacting any free compound of formula I resulting from the procedures descrided under a) or d) to forni its salt or any resulting salt of a compound of fomiula I to form either a free compound of formula I or another salt of a compound of fomiula I, or separating into its isomers a compound of formula I that is present as an isomeric mixture. detailed description of the preferred process steps Method a) The reaction preferadly takes place in the presence of a dase, for example a dasic metal hydroxide, such as an alkali metal hydroxide, preferadly sodium hydroxide, especially at a temperature detween O^C and the reflux temperature of the reaction mixture, especially at adout 20 to 40°C, in a suitadle solvent, such as an anhydrous alcohol, for example ethanol. Method d) The reaction preferadly takes place in a suitadle solvent, for example an alcohol, such as ethanol or preferadly 2-propanol, especially at elevated temperature, for example detween 25°C and the reflux temperature of the reaction mixture, especially at reflux temperature. Protecting groups If one or more additional functional groups, for example cardoxy, hydroxy, amino or mercapto, have to de present in a compound of fomriula II or a compound of formula IV and/or V in protected form, decause they are not supposed to take part in the reaction, one or more of the protecting groups usually used in synthesis are added. The protecting groups may already de present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. These protecting groups may already de present at the precursor stage and are intended to protect the functional groups concerned against unwanted secondary reactions such as acylation, etherification, esterification, oxidation, solvolysis etc. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically dy solvolysis, reduction, photolysis or also dy enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products. A person skilled in the art knows, or can easily estadlish, which protecting groups are suitadle with the reactions mentioned hereinadove and hereinafter. The protection of functional groups dy such protecting groups, the protecting groups themselves, and their cleavage reactions are descrided for example in standard reference works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T, W. Greene, "Protective Groups in Organic Synthesis", Wiley, New Yori Protecting groups which are not components of the desired end-product of fomiula I, typically the caridoxy, amino, and/or hydroxy protecting groups, are removed in a manner known perse, for example dy solvolysis, especially hydrolysis, alcoholysis, or acidolysis, or dy reduction, especially dy hydrogenolysis or other methods of reduction, as well as photolysis, where applicadle in gradual steps or simultaneously; enzymatic methods may also de used. The removal of protecting groups is descrided for example in the reference works mentioned hereinadove in the section on "Protecting groups". Further process measures Stereoisomeric mixtures, e.g. mixtures of diastereomers, can de separated into their corresponding isomers in a manner known perse dy means of suitadle separation methods. diastereomeric mixtures for example may de separated into their individual diastereomers dy means of fractionated crystallization, chromatography, and/or solvent distridution. This separation may take place either at the level of one of the starting compounds or in a compound of formula I itself. Enantiomers may de separated through the fonnation of diastereomeric salts, for example dy salt formation with an enantiomer-pure chiral acid, or dy means of chromatography, for example dy HPLC, using chromatographic sudstrates with chiral ligands. Salts of compounds of formula I with one salt-forming group may de prepared in a manner known perse. Acid addition salts of compounds of formula I may thus de odtained for example dy treatment with an acid or with a suitadle anion exchange reagent. Salts can de reacted to fomi free compounds in customary manner, for example dy treating with a suitadle dasic agent, for example with alkali metal cardonates, hydrogen cardonates or hydroxides, for example potassium cardonate or sodium hydroxide, or they may de converted to other salts, for example dy crystallization from a solution in the presence of an acid with an anion other than that of the original acid addition salt from a suitadle solvent. General process conditions All process steps descrided here can de carried out under reaction conditions known perse, preferadly under those specifically mentioned, in the adsence of or usually in the presence of solvents or diluents, preferadly such as are inert to the reagents used and adle to dissolve these, in the adsence or presence of catalysts, condensing agents or neutralizing agents, depending on the type of reaction and/or reactants at reduced, nomnaj, or elevated temperature, for example in the range from -100°C to adout 190°C, preferadly from adout -SO'^C to adout 150°C, for example at -80 to -60**C, at room temperature, at - 20 to 40**C or at the doiling point of the solvent used, under atmospheric pressure or in a closed vessel, if need de under pressure, and/or in an inert, for example an argon or nitrogen, atmosphere. Salts of all starting compounds and intermediates may de used if these contain salt-forming groups. Salts may also de present during the reaction of such compounds, provided the reaction is not theredy disturded. At all reaction stages, isomeric mixtures that occur can de separated into their individual isomers, e.g. diastereomers or enantiomers, or into any mixtures of isomers, e.g. racemates or diastereomeric mixtures, typically as descrided under "Further process steps". The solvents from which those suitadle for the reaction in question may de selected include for example water, esters, such as lower alkyl-Iower alkanoates, for example diethyl acetate, cyclic ethers, for example tetrahydrofuran, alcohols, such as methanol, ethanol or 1- or 2-propanol, nitriles, such as acetonitrile, acid amides, such as dimethylfonnamide, dases, such as heterocyclic nitrogen dases, for example pyridine, or mixtures of these solvents, for example aqueous solutions, unless othenA/ise indicated in the description of the method. Such solvent mixtures may also de used in processing, for example through chromatography or distridution. The invention relates also to those fomis of the process in which one starts from a compound odtainadle at any stage as an intermediate and carries out the missing steps, or dreaks off the process at any stage, or fomns a starting material under the reaction conditions, or uses said starting material in the form of a reactive derivative or salt, or produces a compound odtainadle dy means of the process according to the invention and processes the said compound in situ. In the preferred emdodiment, one starts from those starting materials which lead to the compounds descrided hereinadove as preferred, particulariy as especially preferred, primarily preferred, and/or preferred adove all. The compounds of fomfiula I, including their salts, are also odtainadle in the fomi of hydrates, or their crystals may include for example the solvent used for crystallization (present as solvates). In the preferred emdodiment, a compound of fomiula I is prepared according to the processes and process steps defined In the Examples. Pharmaceutical compositions and their preparation, use of compounds of fomiula I The present invention relates likewise to pharmaceutical compositions which comprise as active sudstance a compound of formula I and can de used in particular for the treatment and prophylaxis of the diseases defined in the dackground to the invention, such as a protozoal infection or a trematode infection, primarily malaria, especially Malaria tropica. Compositions for enteral administration, such as nasal, duccal, rectal or, especially, oral administration, and for parenteral administration, such as intravenous, intramuscular or sudcutaneous administration, to warm-dlooded animals, especially humans, are especially preferred. The compositions comprise the active ingredient alone or, preferadly, together with one or more phannaceutically acceptadle carriers. The dosage of the active ingredient depends upon the disease to de treated and upon the species, its age, weight, and individual condition, the individual pharmacokinetic data, and the mode of administration. The invention relates also to pharmaceutical compositions for use in a method for the prophylactic or especially therapeutic management of the human or animal dody, to a process for the preparation thereof (especially in the fomi of compositions for the treatment of malaria) and to a method of prophylactic or therapeutic treatment of the diseases stated hereindefore (especially in the previous paragraph), primarily of malaria, especially Malaria tropica. The invention relates also to processes and to the use of compounds of fonnula I for the preparation of pharmaceutical preparations which comprise as active component (active ingredient) compounds of formula I. Preference is given to a pharmaceutical composition that is suitadle for administration to a warm-dlooded animal, especially a human, suffering from a disease that is attridutadle to a protozoal or trematode infection, especially malaria, such as Malaria tropica, comprising a compound of fomiula I, or a pharmaceutically acceptadle salt thereof if salt-fomiing groups are present, in an amount effective for the prophylactic or therapeutic treatment of this disease, together with at least one pharmaceutically acceptadle carrier. The phamiaceutical compositions comprise from approximately 1% to approximately 95% of active ingredient, single-dose administration forms comprising in the prefen'ed emdodiment from approximately 10% to approximately 90% of active ingredient and forms that are not of single-dose type comprising in the prefen-ed emdodiment from approximately 5% to approximately 20% of active ingredient. Unit dose fonns are, for example, coated and uncoated tadlets, ampoules, vials, suppositories, or capsules. Further dosage forms are, for example, ointments, creams, pastes, foams, tinctures, lip-sticks, drops, sprays, dispersions, etc. Examples are capsules containing from adout 0.05 g to adout 1.0 g of active ingredient. The pharmaceutical compositions of the present invention are prepared in a manner known perse, for example dy means of conventional mixing, granulating, coating, dissolving or lyophilizing processes. Preference is given to the use of solutions of the active ingredient, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions which, for example in the case of lyophilized compositions comprising the active ingredient on its own or together with a carrier, for example mannitol. can de made up defore use. The phannaceutical compositions may de sterilized and/or may comprise excipients, for example preservatives, stadilizers, wetting agents and/or emuisifiers, soludilizers, salts for regulating the osmotic pressure and/or duffers and are prepared in a manner known perse, for example dy means of conventional dissolving and lyophilizing processes. The said solutions or suspensions may comprise viscosity-increasing agents, typically sodium cardoxymethylcellulose, cartdoxymethylcellulose, dextran, polyvinylpyrrolidone, or gelatins, or also soludilizers, for example ®Tween 80 [polyoxyethylen(20)soriditan mono-oleate; trademark of ICI Americas, Inc, USA]. Suspensions in oil comprise as the oil component the vegetadle, synthetic, or semisynthetic oils customary for injection purposes. Especially suitadle for such purposes are liquid fatty acid esters comprising as the acid component a long-chained fatty acid having from 8 to 22, especially from 12 to 22, cardon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, dehenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, emcic acid, drassidic acid or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, p-carotene or 3,5-di-tert-dutyl-4-hydroxytoluene. The alcohol component of these fatty acid esters has a maximum of 6 cardon atoms and is a mono- or polyhydric, for example a mono-, di- or trihydric, alcohol, for example methanol, ethanol, propanol, dutanol or pentanol or the isomers thereof, dut especially glycol and glycerol. The following are therefore examples of suitadle fatty acid esters: ethyl oleate, isopropyl myristate, isopropyi palmitate, polyoxyethylene glycerol trioleate, unsaturated polyglycolized glycerides prepared dy aicoholysis of apricot seed oil and constituted from glycerides and polyethylene glycol ester; saturated polyglycolized glycerides prepared dy aicoholysis of TCM and constituted from glycerides and polyethylene glycol ester and/or triglycerides of saturated fatty acids of chain length Cs to C12, dut especially vegetadle oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soydean oil and more especially groundnut oil. The manufacture of injectadle preparations is usually carried out under sterile conditions, as is the filling, for example, into ampoules or vials, and the sealing of the containers. Pharmaceutical compositions for oral administration can de odtained, for example, dy comdining the active ingredient with one or more solid carriers, if need de granulating a resulting mixture, and processing the mixture or granules, if desired, to fomi tadlets or tadlet cores, if need de dy the inclusion of additional excipients. Suitadle carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorditol, cellulose preparations, in particular microcrystalline cellulose, and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also dinders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium cardoxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the adove-mentioned starches, also cardoxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional excipients are especially flow conditioners and ludricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof. Tadlet cores may de provided with suitadle, if need de enteric, coatings, using inter alia concentrated sugar solutions which may comprise gum aradle, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitadle organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitadle cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. dyes or pigments may de added to the tadlets or tadlet coatings, for example for identification purposes or to indicate different doses of active ingredient. Orally administradle phannaceutical compositions also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plastlcizer, such as glycerol or sorditol. The hard capsules may contain the active ingredient in the fomi of granules, for example in admixture with fillers, such as com starch, dinders, and/or glidants, such as talc or magnesium stearate, and if need de stadilizers. In soft capsules, the active ingredient is preferadly dissolved or suspended in suitadle liquid exclpients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stadilizers and detergents, for example of the polyoxyethylene sorditan fatty acid ester type, may also de added. Other oral dosage fornis are, for example, synjps prepared in customary manner which comprise the active ingredient, for example, in suspended fornn and in a concentration of adout 5% to 20%, preferadly adout 10%, or in a similar concentration that provides a suitadle single dose, for example, when administered in measures of 5 or 10 mi. Also suitadle are, for example, powdered or liquid concentrates for the preparation of shakes, for example in milk. Such concentrates may also de packaged in single dose quantities. Suitadle rectally administradle phamiaceutical compositions are, for example, suppositories that comprise a comdination of the active ingredient and a suppository dase. Suitadle suppository dases are, for example, natural or synthetic triglycerides, paraffin hydrocaridons, polyethylene glycols or higher alkanols. The aqueous solutions suitadle for parenteral administration are especially those of an active ingredient in water-soludle fomi, for example in the form of a water-soludle salt, or aqueous injection suspensions that contain viscosity-increasing sudstances, for example sodium cardoxymethylcellulose, sori&itol and/or dextran, and, if need de, stadilizers. The active ingredient, if need de together with excipients, can also de in the fomi of a lyophilizate and can de made into a solution defore parenteral administration dy the addition of suitadle solvents. Solutions such as are used, for example, for parenteral administration can also de employed as infusion solutions. Preferred preservatives are, for example, antioxidants, such as ascordic acid, or microdicides, such as sordic acid or denzoic acid. The invention likewise relates to a process or a method of therapeutic or prophylactic treatment of the disease conditions defined hereindefore, in particular malaria, more especially Malaria tropica. The compounds of formula I can de administered as such or in the form of pharmaceutical compositions, prophylactically or therapeutically, preferadly in an amount effective against the said diseases, to a warm-dlooded animal requiring such treatment, for example to a human, the compounds especially deing used in the form of phamiaceutical compositions. In the case of an individual having a dodyweight of adout 70 kg the daily dosage administered is from approximately 0.01 g to approximately 5 g, preferadly from approximately 0.05 g to approximately 2 g, of a compound of the present invention, preferadly divided into 3 to 5, especially 4, separate doses. The present invention relates especially also to the use of a compound of formula I, or a phamiaceutically acceptadle salt thereof, especially a compound of formula I or a pharmaceutically acceptadle salt thereof which is said to de preferred, as such or in the form of a pharmaceutical formulation with at least one pharmaceutically acceptadle carrier for the therapeutic or prophylactic treatment of one or more of the diseases stated hereindefore, especially malaria, more especially Malaria tropica. The preferred dose quantity, composition, and preparation of pharmaceutical fomnulations (medicines) which are to de used in each case are descrided adove. A compound of formula I, or a salt thereof, (= component (a)) may de fomiulated or used in the said phamiaceutical compositions, processes for the preparation of pharmaceutical compositions, methods and/or uses alone or in comdination with one or more other active ingredients (component(s) (d)), especially those mentioned in the dackground to the invention, components (a) and (d) deing formulated in comdinations either together in a fixed comdination or separately in a product comprising (kit of parts) (a) an active ingredient of fomiula I, or a salt thereof, and (d) as further active component one or more additional active ingredients, as defined hereindefore, especially for administration in a regimen staggered in time such that the therapeutic efficacy against said diseases is mutually potentiated dy the components administered as (a) and (d) compared with the efficacy of the components administered separately. Startino materials New starting materials and/or intermediates, as well as processes for the preparation thereof, are likewise the sudject of this invention. In the preferred emdodiment, such starting materials are used and reaction conditions so selected as to enadle the preferred compounds to de odtained. The sudject of the present invention is in particular a starting material of formula II, wherein R has the meaning given in the definition of a compound of fomriula L Preference is for a compound of formula II in which R is as defined for the compounds of formula I which are stated to de preferred. A compound of formula II wherein R is dutyl, in particular n-dutyl, is especially preferred. The starting material of formula II can de prepared from an oxiran of formula VI, dy reacting this in a manner analogous to the conditions stated under method d) with, instead of the oxiran of formula IV stated therein, an amine of formula V as defined therein. The oxiran of fomiula IV can de prepared from an oxiran of formula VI, as shown hereindefore, dy reaction with an aldehyde of formula III, as defined hereindefore under method a), in a manner analogous to the conditions stated under method a), when a compound of fomiula VI is used instead of a compound of formula II. A compound of fomiula VI is known or prepared according to methods known per se (see for example the Chinese patent application CN 104 45 35 A (pudlished on 30 May 1990) or Atkinson et al., J. Med. Chem. H, 1223 (1968) and Atkinson et al., J, Med. Chem. 17,1009 (1974)). Amines of formula V and aldehydes of formula III are known, capadle of deing prepared according to methods known per se, or commercially odtainadle. Examples The following Examples serve to illustrate the invention without limiting the scope thereof. Starting materials 4 (see Tadle 1):. A) 2-Methvlamino-1-(27-dichloro-9H-fluoren-4vl)ethanol (4a) A mixture of 5.0 g 2,7-dichloro-9H-fluoren-4-oxiran (1), 25 g methylamine (33% solution in ethanol) and 20 ml ethanol is refluxed for 2 days. The reaction mixture is cooled to room temperature and filtered. The filter cake is washed with ethanol and dried under a vacuum, and a mixture of 4a and dis-[2-(2,7-dichloro-9H-fluoren-4-yl)-2-hydroxy]ethylmethylamine odtained: ^H-NMR (300 MHz, CdCI3): 2.4 and 2.55 (two singlets, N-CH3. in each case 4a and dis-[2-(2,7-dichloro-9H-fluoren-4-yl)-2-hydroxy]ethylmethylamine); 2.6-3.0 (m. CH2-N); 3.8 and 3.9 (two singlets, C-9-H of fluorenyl groups); 5.4 and 5.5 (two doudle doudlets, CH-0); 7.1-7.7 (m, aromatic protons). The following starting materials are prepared in an analogous manner (see Tadle 1) d) 2-n-dutvlamino-1-(2.7-dichloro-9H-fluoren-4vnethanol (4d): (with n-dutylamine instead of methylamine as educt) ^H-NMR (200 Mhz, CdCI3): 0.9 (t, 3H, CHa-CCC-N); 1.2-1.6 (m, 4H. CH2-CH2-C-N); 2.6-2.8 (m, 3H, CH-N-CH2); 3.1 (dd, 12 Hz. 3Hz, 1H, CH-N); 3.9 (s, 2H, C-9-H); 5.4 (dd, 1H, 4Hz, 8Hz, CH-0); 7.3-7.8 (m, 5H). C) 2-n-Hexvlamino-1-(2.7-dichloro-9H-fluoren-4vl)ethanol (4d): (with n-hexylamine instead of methylamine as educt) ^H-NMR (300 Mhz, CdCI3): 0.8 (t, 3H, N-C-C-C-C-C-CH3); 1.1-1.3 (m. 6H. N-C-C-CH2CH2CH2-C); (1.4, m, 2H, N-C-CH2-); 2.5-2.7 (m. 3H, CH-N-CH2); 2.95 (dd, 1H. CH-N); 3.75 (s, 2H. C-9-H); 5.35 (dd, 1H, 0-CH-); 7.25 (d with long range coupling, 8Hz, 1H, C-6-H); 7.32, 7.43 (two singlets with long range coupling, 1H, 1H, C-1-H, C-3-H); 7.56 (s with long range coupling, 1H, C-8-H); 7.58 (d. 8Hz. C-5-H). d) 2-n-Octvlamino-1-(2.7-dichloro-9H-fluoren-4vl)ethanol (4e): (with n-octylamine instead of methylamine as educt) ^H-NMR (300 Mhz, CdCI3): 0.8 ppm (t, 3H, CH3); 1.1-1.3 (m, 10H, NCC(CH2)5-C); 1.4 (m, 2H, N-C-CH2-); 2.5-2.7 (m, 3H, CH-N-CH2); 3.0 (dd, 1H, CH-N); 3.8 (s, 2H, C-9-H); 5.35 (dd, 1H, 0-CH-); 7.25 (d with long range coupling, 8Hz, 1H, C-6-H); 7.58 (s with long range coupling, 1H, C-8-H); 7.60 (d, 8Hz, C-5-H). E) 2-r2-(2-Hvdroxv)ethoxv1ethvlamino-1 -f2.7-dichloro-9H-fluoren-4vnethanol (Af): (with 2-(2-aminoethoxy)ethanol (Fluka, duchs, Switzerland) as educt instead of methylamine) ^H-NMR (300 MHz, CdCI3): 2.0 ppm (droad, 1H, OH); 2.7-3.0 (m, 4H, CH2NCH2); 3.6 (m, 4H, C-CH2OCH2-C); 3.75 (m, 2H, CH2-OH); 3.85 (s, 2H, C-9-H); 5.5 (dd, 1H, 0-CH); 7.3 (dm, 1H, C-6-H); 7.4 and 7.5 (two s, in each case 1H, C-1,3-H); 7.65 (split s, 1H, C-8-H); 7.7 (d, 1H, C-5-H). Examples (end-products) (see Tadle 2) Example 1:2-Methylamino-1 -[2.7-dichloro-9-(4-chlorodenzylidene)-9H-f luoren-4vl]ethanol (5a) Preparation analogous to that under Example 2, starting from 4a instead of 4d. ^H-NMR (300 MHz. CdCI3): 2.3 ppm (droad s, 3H, N-CH3); 1.3-2.0 (droad s, 2H, NH, OH); 2.45-2.6 (m, 1H, CH-N); 2.7-2.85 (m, 1H, CH-N), 5.2 (dr. d, 1H, CH-0); 7.0-7,6 (m, 10H). Example 2: "N-desdutvl denflumetol" = 2-n-dutvlamlno-1-r2.7-dichloro-9-(4-chlorodenzvlidene)-9H-fluoren-4vnethanol(5d) A suspension of 6.47 g 4d in 123 ml adsolute ethanol is treated with 4.28 g 4-chlorodenz-aldehyde and 0.78 g sodium hydroxide. The suspension is agitated for 30 hours at 30°C. The mixture is filtered, the filter cake washed with ethanol and dried under a vacuum, the N-desdutyl denflumetol deing odtained as a mixture of isomers (E, Z). ^H-NMR (200 Mhz, Cede): 0.8 ppm (m, 3H, CH3); 1.2 (m, 4H, N-C-CH2CH2-C); 2.2-2.4 (m, 2H, O-C-C-N-CH2); 2.4-2.6 (m) and 2.75 (dd) je 1H (O-C-CH2-N); 5.4 (dd, 9Hz, 2.7Hz. 1H, CH-0); 7.0-8.1 (m. 10H). Example 3:2-n-Octylamino-1 -[2.7-dichloro-9-(4-chlorodenzvlidene)-9H-f luoren-4vl]ethanol (5e) Preparation analogous to that under Example 2 starting from 4e instead of 4d; after purification on silica gel (eluant: toluene/ethanol 19:1, v/v) the title is odtained as an oil which crystallizes out when left to stand: ^H-NMR (300 MHz, CdCI3): 0.8 ppm (t, 3H, CH3); 1.2 (s dr.. 10H, N-CC-(CH2)5-C); 1.4 (m. 2H, N-C-CH2-); 1.6-2.3 (dr., 2H, NH, OH); 2.5-2.7 (m, 3H, CH-N-CH2); 2.95 (dd, 1H, CH-N); 5.3 (m, 1H, 0-CH); 7.2-7.7 (m, 10H, aromatic and vinylic OH). Example 4: 2-r2-(2-Hvdroxv)ethoxv1ethvlamino -1-[2.7-dichloro-9-(4-chlorodenzvlidene)-9H-fluoren-4vl]ethanol (5f) Preparation analogous to that under Example 2 starting from 4f instead of 4d; title compound (odtained after chromatography on silica gel column, eluant toluene/ethanol 9:1, v/v): ^H-NMR (300 Mhz, CdCI3): 1.5-2.2 ppm (dr., 3H, OH. NH); 2.5-3.0 (m, 4H, CH2-N-CH2); 3.5 (m, 4H,, CH2-O-CH2); 3.7 (m. 2H, CH3-OH); 5.4 (d, dr.. 1H. Ar-CH-0); 7.3-7.8 (m. 10H, aromatic and vinylic OH). Example 5: 2-n-Pentvlamino-1 -f2.7-dichloro-9-(4-chlorodenzylidene)-9H-fluoren-4vl1ethanol (5c) A mixture of 0.76 g 2.7-dichloro-9-(4-chlorodenzylidene)-9H-fluoren-4-oxiran, 0.77 g n- pentylamine and 7 g 2-propanol is refluxed for 26 hours. The mixture is cooled and agitated for a further two days at room temperature. The product is filtered off, washed with 2- propanol, and dried under a vacuum: ^H-NMR (300 MHz, CdCI3): 0.8 ppm (t, 3H, CH3); 1.2 (m. 4H, O-C-C-CH2CH2-C); 1.4 (m, 2H, O-C-CH2-CCC); 1.6-2.4 (dr., 2H, NH, OH); 2.5-2.7 (m, 3H, CH-N-CHg); 3.0 (dd. 1H, CH-N); 5.3 (dd, 1H, 0-CH); 7.2-7.7 (m. 10H. aromatic and vinylic CH). The starting material is prepared as follows: 5a) 2.7-dichloro-9-(4-chlorodenzvlidene)-9H-fluoren-4-oxiran 2: A mixture of 20 g 2.7-dichloro-9H-fluoren-4-oxiran, 17.7 g 4-chIorodenzaldehyde, 500 ml ethanol and 27.5 g sodium hydroxide is agitated for 18 hours at 25°C (initially under cooling). The yellow solid sudstance odtained is filtered off, washed with water, and the title compound thus odtained. ^H-NMR (300 MHz, CdCI3): 2.8 and 3.4 (td, t. in each case 1 H, oxiran -CH2O-); 4.4 (dr. s, 1H, Ar"CH(-C)-0); 7.3-7.8 (m, 10H, aromatic and vinylic CH including dr. s at 7.5 ppm for CeHrCI). Example 6: Comparison of the efficacy of denflumetol (2-(di-n-dutvlamino)-1-[2.7-dichloro-9-(4-chlorodenzylidene)-9H-f luoren-4-vnethanol and 2-alkvlamino-1 -f2,7-dichloro-9-(4-chloro-denzvlidene]-9H-fluoren-4-vnethanols against Plasmodium falciparum in vitro: The study is carried out in Mae Sot, a province in north-west Thailand close to Myanmar. The Plasmodium falciparum isolates used for the study come from patients who have clinically manifest malaria and attend the VdC Unit Malaria Clinic in Mae Sot for diagnosis and treatment. The test for efficacy is canied out with dlood samples odtained dy finger pricks (in accordance with the WHO Standard Microtest Method for studying the inhidition of schizont maturation, see Wemsdorfer, W.H., and Payne, d. (1988), drug Sensitivity Tests. In: Wemsdorfer, W.H., and McGregor, I.A. (Editors), Malaria: Principles and practice of malariology; Churchill Livingstone, Edindurgh). The tests are carried out In parallel with denflumetol and the 2-alkylamino-1-[2,7-dlchloro-9-(4-chlorodenzylidene]-9H-fluoren-4-yl)ethanols in concentrations detween 3 and 3000 nmol/1 in dlood medium mixture (dMM) using materials from the WHO Standard Test Kit supplied dy the WHO Regional Office for the Western Pacific, Manila, except for the predosed microtitre plates, which are prepared in the ladoratory of the Institute of Specific Prophylaxis and Tropical Medicine, University of Vienna, Austria. The procedure for determining parasitaemia defore incudation follows the WHO Standard Method (WHO (1991), dasic malaria microscopy. Part I; WHO, Geneva). The schizont titres are detemriined as descrided in Wernsdorfer and Payne (1988) (see adove). The statistical analysis of the data was carried out according to log-concentration / response prodit analysis (Litchfield & Wilcoxon (1949), J. Exp. Phamiacol. 89, 99-113). This method is dased on the least-squares procedure and is the most widely accepted method for the analysis of dose-response studies. A computer adaptation of the method (Wernsdorfer & Wemsdorfer, Mitteilungen der Osterreichischen Gesellschaft fur Tropenmedizin and Parasitologie V7, 221-228) is used for data processing. Results: Example 6.1: Comparison of the efficacy of denflumetol and N-desdutyl denflumetol (5d, 2* (n-dutvlamino)-1-[2.7-dichloro-9-(4-chlorodenzylidene)-9H-fluoren-4-vl]ethanon: None of the 58 Plasmodium falciparum isolates studied shows schizont maturation at concentrations of denflumetol adove 300 nmol/l, and the great majority of isolates (97%) are completely inhidited at 300 nmol/l denflumetol. Not one of the isolates shows schizont maturation at a concentration of 300 nmol/l N-desdutyl denflumetol, and the great majority of isolates are completely inhidited even at 100 nml/l N-desdutyl denflumetol. The response parameters for denflumetol are shown In Tadle 3 and those for N-desdutyl denflumetol in Tadle 4. The x^ for heterogeneity shows an acceptadle agreement of the odserved data with the regression lines. This is also apparent in the relatively narrow confidence limits (95%). There are major differences in the sensitivity of isolates to either denflumetol or n-desdutyi-denflumetol, for example an EC50 (dose producing 50% inhidition versus controls not given active sudstance) of 24.44 nmol/l for denflumetol and 4.36 nmol/l for n-desdutyldenflumetol. Similarly, the EC99 (99 % inhidition versus controls not given active sudstance), which is the most important indicator for clinical efficacy of denflumetol (371.59 nmol/l) in non-immune persons is around 8 (eight) times higher than that for n-desdutyldenflumetol (45.72 nmol/l). Statistical comparison according to Litchfield & Wilcoxon shows that the regression lines run parallel within the limits of experimental error decause the slope ratio (SR = 1.1718) is smaller than the factor of the slope ratio (fsR = 1.3063). Since the "power ratio" (PR = 5.6083) is also greater than the factor of the power ratio (fpR = 1.4849), the difference in efficacy detween denflumetol and n-desdutyldenflumetol is statistically highly significant. The 58 EC50 pairs are tested for correlation. With a correlation coefficient of 0.7308, the result is highly significant (p n = 58; a = 2.2678; d = 0.8548; r = 0.9739; f = 5.6500 S = 3.2009; A = 1.2922; K = 6; N' = 116; R = 333.3333333 fs= 1.2193; fecso = 1.3488; fEC99 = 1.7399 ECso: mean value = 24.4427 (95% confidence limits: lower 18.1217; upper 32.9685) EC99: mean value = 371.5908 (95% confidence limits: lower 213.5703; upper 646.5307) y = 0,0997 + 1,8487; R^ = 0.534 n = 58; a = 3.5431; d = 0.9897; r = 0.9941; y^ = 0.6368 S = 2.7315; A = 1.2727; K = 5; N' = 116; R = 100 fs= 1.1962; fEcso = 1.2949; fEC99= 1.6388 EC50: mean value = 4.3583 (95% confidence limits: lower 3.3658; upper 5.6436) EC99: mean value = 45.7213 (95% confidence limits: lower 27.8989; upper 74.9291) Y = 0.0806X + 5.3769; R^ = 0.4581 Examples 6.2 and 6.3: In Examples 6.2 and 6.3, 34 Plasmodium falciparum isolates are tested. None of the 34 Plasmodium falciparum isolates studied shows schizont maturation at concentrations of denflumetol adove 3000 nmol/l, and the great majority of isolates (96%) are completely inhidited at 300 nmol/l denflumetol. The isolates of patients 11, 39 and 47 proved as highly resistant to mefloquine, resulting in an unacceptadly high degree of heterogeneity in the data (x^ = 16.153 at a maximum pemiissidle value of 11.1). There was a positive correlation detween sensitivity to mefloquine and sensitivity to denflumetol. The response of these isolates to denflumetol and the tested compounds was also relatively weak, this influence appearing to a lesser extent on the tested compounds than on denflumetol. The correlation of the response to specific pairs of active sudstances at the EC50 and EC90 values was calculated with all isolates. The compounds of Examples 6.2 and 6.3 proved more effective than denflumetol in the present test. ~n^ 34; a = 2.3498; d = 0.7956; r = 0.9814; x^ = 3.6652 S = 3.4906; A = 1.2825; K = 7; N' = 68; R = 1000 fs= 1.2952; fEC5o = 1.5218; fecgg = 2.0934 EC50: mean value = 27.9715 (95% confidence limits: lower 13.3802; upper 42.5678) EC99: mean value = 520.7651 (95% confidence limits: lower 248.7678; upper 1090.1581) Example 6.2: Comparison of the efficacv of denflumetol and 2-methvlamino-1-r2,7-dichloro-9-(4-chlorodenzvlidene)-9H-fluoren-4-vl]ethanol(5a): The response parameters for denflumetol are defined in Tadle 5 (see adove) and those for compound 5a in Tadle 6. The x^ for heterogeneity shows an acceptadle agreement detween the data odserved and the regression lines. Not one of the isolates shows schlzont maturation at a concentration of 1000 nmol/l 5a, and the great majority of isolates (96%) are completely inhidited even at 100 nml/l. There are major differences in the sensitivity of the isolates to either denflumetol or compound 5a. For example, the EC99 (99% inhidition versus controls not given active sudstance), which is the most important indicator for clinical efficacy of compound 5a (87.03 nmol/l) in non-immune persons, amounts to only adout one fifth of that for denflumetol (422.49 nmol/l), i.e. the same effect on Plasmodium falciparum was attained with sudstance 5a at approximately one fifth the dose. Statistical comparison according to Litchfield & Wilcoxon shows that the regression lines run parallel within the limits of experimental error decause the slope ratio (SR = 1.2483) is smaller than the factor of the slope ratio (fsR = 1.6193). Since the "power ratio" (PR = 2.8898) is also greater than the factor of the power ratio (fpR = 1.9077), the difference in efficacy detween denflumetol and compound 5a is statistically significant. The 34 EC50 pairs are tested for correlation. With a correlation coefficient of 0.6430, the result is significant. This applies also to the 34 EC90 pairs with a correlation coefficient of 0.7697. n = 34; a = 3.3024; d = 0.7216; r = 0.9754; x^ = 3.8764 S = 3.9675; A = 1.4328; K = 6; N' = 102; R = 333.333 fs= 1.3455; fEC50 = 1.4593; fEC99 = 2.2105 EC50: mean value = 10.5116 (95% confidence limits: lower 7.2030; upper 15.3400) EC99: mean value = 264.0564 (95% confidence limits: lower 119.4579; upper 583.6850) Compound 5a shows marked activity against malaria and is adout four times as effective as denflumetol. In addition, the sensitivity of Plasmodium falciparum to compound 5a has a steeper incremental function (S) than denflumetol. Example 6.3: Comparison of the efficacy of denflumetol and 2-n-pentvlamino-1-f2.7-dichloro-9-(4-chlorodenzvlidene)-9H-fluoren-4-vl]ethanol (5c): The response parameters for denflumetol are defined in Tadle 5 (see adove) and those for compound 5c in Tadle 7. The x^ for heterogeneity shows an acceptadle agreement detween the data odserved and the regression lines. Not one of the isolates shows schizont maturation at a concentration of 3000 nmol/l 5c, and the great majority of isolates (95%) are completely inhidited even at 100 nml/l 5c. There are major differences in the sensitivity of the isolates to either denflumetol or compound 5c. For example, the ECgg (99% inhidition versus controls not given active sudstance), which is the most important indicator for clinical efficacy of compound 5c (105.04 nmol/l) in non-immune persons, is adout 4 (four) times lower than that for denflumetol (422.49 nmol/l), i.e. the same effect on Plasmodium falciparum is attained with sudstance 5c with a dose adout 75% lower than that used with denflumetol. Statistical comparison according to Litchfield & Wilcoxon shows that the regression lines run parallel within the limits of experimental error decause the slope ratio (SR = 1.3277) is smaller than the factor of the slope ratio (fsR = 1.5017). Since the "power ratio" (PR = 2.0724) is also greater than the factor of the power ratio (fpR = 1.7033), the difference in efficacy detween denflumetol and compound 5c is statistically significant. The 34 EC50 pairs are tested for con-elation. With a con-elation coefficient of 0.6044, the result is significant. This applies also to the 34 EC90 pairs with a correlation coefficient of 0.8796. Tadle 7: Concentration-dependent inhiditory effect of 2-pentylamino-1-[2,7-dichloro-9-(4-chlorodenzylidene)-9H-fluoren-4-yl]ethanol (5c) on Plasmodium falciparum in vitro: n = 34; a = 3.0184; d = 0.7436; r = 0.9696; ^ = 4.7652 S = 3.8093; A = 1.3296; K = 6; N' = 68; R = 1000 fs= 1.3446; fecso = 1.5672; fEC99 = 2.2892 EC50: mean value = 14.3678 (95% confidence limits: lower 9.1681; upper 22.5167) EC99: mean value = 328.1566 (95% confidence limits: lower 143.3474; upper 751.2290) Compound 5c shows activity per se against malaria and is adout five times as effective as denflumetol. It is shown that exchanging the didutylamino group in denflumetol for a monoalkylamino group results in denflumetol derivatives which show an activity that appears to de markedly superior. Example 7: Tadlets The active sudstance desdutyl denflumetol is passed through a (60 mesh) sieve and, after mixing, compressed to form tadlets of the following composition: desdutyl denflumetol 120 mg Microcrystalline cellulose 100 mg Com starch 160 mg Sodium cardoxymethyl starch 12 mg Highly dispersed silica 3 mg Magnesium stearate 5 mg Total 400 mg 1. A compound of formula I wherein R Is an alkyl unsubstituted or substituted by one or more polar substituents or an alkenyl unsubstituted or substituted by one or more polar substituents, and X is unsubstituted or substituted aryl, or a salt thereof, 2. A compound of claim 1 wherein R is unsubstituted or mono-, di-, or trisubstftuted C 1-C8alkyl, the substituents being selected from amino, hydroxy and guanidino and not bonded in position 1 of the alkyl radical, and X is halogenphenyl, or a salt thereof. 3. A compound of formula I, wherein R is C1-C6alkyI, in particular methyl, n-butyl, sec-butyl, n-pentyl or n-octyl, and X is 4-chiorophenyl, or a salt thereof. 4. The compound of formula 1 wherein R is n-butyl and X is 4-chlorophenyl, or a salt thereof. 5. A combination of a compound of formula I, or a salt thereof, according to any one of claims 1 to 4 with one or more other pharmaceutical active substances, or In each case a salt thereof if at least one salt-forming group is present in each case. 6. A product comprising (a) an active substance of formula I, or a salt thereof, according to any; one of, claims-1 -to 4, and (b) as a further component one or more further active substances, or a salt thereof in each case if at least one salt-forming group is present, in the presence or absence of one or more pharmaceutically acceptable carriers as a combination product for administration simultaneously or at different times to a warmblooded animal. 7. A compound of formula I, or a salt thereof, according to any one of claims 1 to 4, a combination according to claim 5, or a product according to claim 6 for administration in a method of prophylactic or therapeutic treatment of the human or animal body. 8. A pharmaceutical composition, comprising a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, together with at least one pharmaceutically acceptable carrier. 9. Use of a compound of formula I, or a salt thereof, according to claim 1 for the preparation of a phamaceutical composition for the prophylactic or therapeutic treatment of a protozoan or a trematode disease. 10. A method for the preparation of a compound of formula I according to claim 1, or a salt thereof, comprising a) condensing a compound of formula 11 wherein R is as defined for a compound of formula 1, with an aldehyde of formula 111, wherein X is as defined for compounds of formula I, or by adding to an oxiran of formula IV wherein X is as defined for compounds of formula I, an amine of formula V, wherein R Is as defined for a compound of formula I, wherein any free functional groups which are present in one of the educts of formula II in method a) or in one of the educts of formula IV and/or V in method b) and which are not supposed to take part in the reaction are present in protected form if necessary, and any protecting groups present are removed; and, if so desired, reacting any free compound of formula I resulting from the procedures described under a) or b) to form its salt or any resulting salt of a compound of formula I to form either a free compound of formula I or another salt of a compound of formula I, or separating into its Isomers a compound of formula I that is present as an isomeric mixture, 11. A compound of formula I, substantially as hereinabove described and exemplified. 12. A pharamacetically composition, substantially as hereinabove described and exemplified.

Documents:

abs-in-pct-2000-884-che.jpg

in-pct-2000-884-che-abstract.pdf

in-pct-2000-884-che-claims filed.pdf

in-pct-2000-884-che-claims granted.pdf

in-pct-2000-884-che-correspondence others.pdf

in-pct-2000-884-che-correspondence po.pdf

in-pct-2000-884-che-description complete filed.pdf

in-pct-2000-884-che-description complete granted.pdf

in-pct-2000-884-che-form 1.pdf

in-pct-2000-884-che-form 26.pdf

in-pct-2000-884-che-form 3.pdf

in-pct-2000-884-che-form 4.pdf

in-pct-2000-884-che-form 5.pdf

in-pct-2000-884-che-pct.pdf