WO1997044313A1 - N,N'-Di(2-HYDROXYBENZYL)ETHYLENEDIAMINE-N,N'-DIACETIC ACID DERIVATIVES - Google Patents

Abstract

There are described N,N'-di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid hemiesters of the formula (I) wherein R1 to R9 are as defined in the description. The compounds have valuable pharmaceutical properties and are active, in particular, as iron chelators. They can be used for the treatment of an excess of iron in the body of warm-blooded animals.

Description

N.N'-Di(2-hvdroxybenzylιethylenediamine-N,N'-diacetic acid derivatives

The invention relates to compounds of the formula I

in which R¹ is hydrogen or acyl; R² is OR³ or NR⁴R⁵; R³ is unsubstituted or substituted lower alkyl, cyclo-lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or lower alkoxycarboxy-lower alkyl; R⁴ and R⁵ independently of one another are hydrogen or unsub¬ stituted or substituted lower alkyl; R⁶ and R⁷ independently of one another are hydrogen, halogen, lower alkyl or lower alkoxy; R⁸ and R⁹ individually are hydrogen or together are π-butylene; and salts thereof.

In the context of the present application, the general terms used above and below are pref¬ erably defined as follows:

Halogen is, for example, chlorine, bromine or fluorine, but can also be iodine.

The prefix "lower" designates a radical having not more than 7 and in particular not more than 4 carbon atoms.

Alkyl is straight-chain or branched. Per se, for example, lower alkyl, or as a constituent of other groups, for example, lower alkoxy, lower alkoxy-lower alkyl, lower alkoxycarbonyl- lower alkyl, lower alkoxycarboxy-lower alkyl, it can be unsubstituted or substituted, for ex¬ ample by halogen, hydroxyl, trif luoromethyl, cyclo-lower alkyl, amino, lower alkylamino; di- lower alkylamino; it is preferably unsubstituted. Lower alkyl is, for example, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, fert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably methyl, ethyl and n-propyl.

Cyclo-lower alkyl is an unsubstituted or substituted cycloalkyl radical having from 3 to not more than 7 ring members, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo- heptyl.

n-Butylene is the group -(CH₂)₄-.

Lower alkoxy is, for example, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- butoxy, n-amyloxy, isoamyloxy, preferably methoxy and ethoxy.

Lower alkoxy carbonyl designates the radical lower alkyl-O-C(O)- and is, for example, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxy- carbonyl, tert-butoxycarbonyl, π-amyloxycarbonyl, isoamyloxycarbonyl, preferably methoxy- carbonyl and ethoxycarbonyl.

Lower alkoxycarboxy designates the radical lower alkyl-O-C(O)-O- and is, for example, n-propoxycarboxy, isopropoxycarboxy, n-butoxycarboxy, isobutoxycarboxy, sec-butoxy- carboxy, tert-butoxycarboxy, n-amyloxycarboxy, isoamyloxycarboxy, preferably methoxy- carboxy and ethoxycarboxy.

Acyl is the radical Z-C(O)- in which Z is unsubstituted or substituted lower alkyl or lower alk¬ oxy, substituted or unsubstituted aryl or aryloxy.

Aryl per se or as a constituent of other groups, such as aryloxy, designates a six-membered aromatic hydrocarbyl, for example phenyl, which can be unsubstituted or substituted, for example by halogen, hydroxyl, lower alkyl, lower alkoxy.

Salts of compounds of the formula I are, in particular, pharmaceutically acceptable salts, especially salts with bases, such as appropriate alkali metal or alkaline earth metal salts, e.g. sodium, potassium or magnesium salts, pharmaceutically acceptable transition metal salts such as zinc or copper salts, or salts with ammonia or organic amines, such as cyclic amines, such as mono-, di- or tri-lower alkylamines, such as hydroxy-lower alkylamines, e.g. mono-, di- or trihydroxy-lower alkylamines, hydroxy-lower alkyl-lower alkylamines or polyhy¬ droxy-lower alkylamines. Cyclic amines are, for example, morpholine, thiomorpholine, piperidine or pyrrolidine. Suitable mono-lower alkylamines are, for example, ethyl- and fert-butylamme; di-lower alkylamines are, for example, diethyl- and diisopropylamine; and tri-lower alkylamines are, for example, trimethyl- and triethylamine. Appropriate hydroxy- lower alkylamines are, for example, mono-, di- and triethanolamine; hydroxy-lower alkyl- lower alkylamines are, for example, N,N-dimethylamιno- and N.N-diethylaminoethanol; a suitable polyhydroxy-lower alkylamine is, for example, glucosamine. In other cases it is also possible to form acid addition salts, for example with strong inorganic acids, such as mineral acids, e.g. sulfuric acid, a phosphoric acid or a hydrohahc acid, with strong organic carb¬ oxylic acids, such as lower alkanecarboxylic acids, e.g. acetic acid, such as saturated or unsaturated dicarboxylic acids, e.g. malonic, maleic or fumaric acid, or such as hydroxy- carboxyhc acids, e.g. tartaric or citric acid, or with sulfonic acids, such as lower alkane- or substituted or unsubstituted benzenesulfonic acids, e.g. methane- or p-toluenesulfonic acid. Compounds of the formula I having an acidic group, e.g. carboxyl, and a basic group, e.g. ammo, can also be present in the form of internal salts, i.e. in zwitterionic form, or a part of the molecule can be present as an internal salt, and another part as a normal salt. Addition¬ ally included are salts which are unsuitable for pharmaceutical uses, since these can be used, for example, for the isolation or purification of free compounds I and of their pharma¬ ceutically acceptable salts.

The compounds of the formula I have valuable pharmacological properties, primarily a marked binding of trivalent metal ions, in particular those of iron (A. E. Martell and R. J. Motekaitis, "Determination and Use of Stability Constants", VCH Publishers, New York 1992). They are able, as can be shown for example in an animal model using the non-iron overloaded cholodocostomtzed rat (R. J. Bergeron et al., J. Med. Chem. 34, 2072-2078 (1991 ); G. F. Smith, W. H. McCurdy and H. Diehl, Analyst!!, 418-422 (1952)) or the iron- overloaded monkey (R. J. Bergeron et al., β/oodβl , 2166-2173 (1993)) in doses from ap¬ proximately 150 μmol/kg, inter alia, to prevent the deposition of iron-containing pigments and in the case of existing iron deposits in the body cause excretion of the iron. ln various illnesses, in particular of man, an excess of iron occurs in the various tissues. This is designated as iron overload (formerly haemosiderosis). It occurs, for example, after parenteral administration of iron (especially repeated blood transfusions) or after increased uptake of iron from the gastrointestinal tract. Repeated transfusions are necessary in seri¬ ous anaemias, especially in thalassaemia major, the severe form of β-thalassaemia, but also in other anaemias. Increased iron resorption from the gastrointestinal tract either takes place primarily, e.g. on account of a genetic defect (so-called haemochromatosis), or sec¬ ondarily, such as after anaemias in which blood transfusions are not necessary, such as, for example, thalassaemia intermedia, a milder form of β-thalassaemia.

A reduction in the iron(lll) concentration is also of interest for the treatment of disorders due to ιron(lll)-dependent microorganisms and parasites, which is of key importance not only in human medicine, such as in particular in malaria, but also in veterinary medicine. Complex formation with other trivalent metals can also be used for excretion thereof from the organ¬ ism, e.g. for the removal of aluminium in dialysis encephalopathy and osteomalacia, and also in Alzheimer's disease. A number of further applications are also described in the lit¬ erature, e.g. by G. Kontoghiorghes, Toxicology Lett. 80, 1-18 (1995).

Desferπoxamine B has already been known for a long time and used therapeutically for these purposes (H. Bickel, H. Keberle and E. Vischer, Helv. Chim. Acta 46, 1385-9 [1963]). A disadvantage of this preparation, however, turns out to be the fact that desferπoxamine and its salts only have a low, inadequate activity on oral administration and require a par¬ enteral administration form in all of the abovementioned application possibilities. It is thus recommended, for example, as a particularly effective method to administer the active sub¬ stance by means of a slow (8- to 12-hour) subcutaneous infusion, which, however, de¬ mands the use of a portable mechanical device, such as an infusion syringe actuated by an electrical drive. Apart from their awkwardness, such solutions are affected by a high treat¬ ment cost, which severely restricts their use; in particular a comprehensive treatment of the thalassaemias in the countries of the Mediterranean region, of the Middle East, India and South-East Asia, of malaria worldwide and of sickle-cell anaemia in African countries is made impossible. These widespread diseases are furthermore a serious problem for the health service in these countries and make the search for a simpler and more inexpensive therapy, preferably by means of an orally active preparation, the urgent object in this area. ln L'Eplattemer et al., New Multidentate Ligands. VI. Chelating Tendencies of N,N'-Dι- (2-hydroxybenzyl)ethylenediamine-N,N'-diacetic Acid, J. Am. Chem. Soc. 89(4), 837-843 (1967), the complex formation properties of N,N'-di(2-hydroxybenzyl)ethylenedιamιne- N,N'-diacetic acid (= [{2-[carboxymethyl-(2-hydroxybenzyl)amino]ethyl}-(2-hydroxybenzyl)- aminojacetic acid, in the following called HBED) and the stability constants with various metals, inter alia also with iron in the form of its trivalent cations (Fe^3*), are described. US 3,632,637 discloses a synthesis of this compound. CG. Pitt, US 4,528,196 and CG Pitt et al., Esters and Lactones of Phenolic Amino Carboxylic Acids: Prodrugs for Iron Chelation, J. Med. Chem. 29, 1231-1237 (1986) come to the conclusion that HBED diesters can be used as iron chelators, even in oral form, for the treatment of the excess of iron in thalassaemia and other illnesses, esterification leading to a prodrug from which the actual active substance HBED is released in the body; the diesters themselves only have a low af¬ finity for iron. This concept is taken up in WO 95/16663 and continued with novel esters which should favour absorption.

Prodrugs, however, in general require that suitable enzyme systems or a suitable chemical medium is present in the body, which make possible the release of the actual active ingre¬ dient Moreover, the radicals removed, which can also be described as protective groups removable under physiological conditions, if appropriate - depending on the type of radicals - lead to undesired side effects.

The compounds according to the invention are excellently absorbed by the body on oral administration and, in contrast to the previously described diesters, have a high affinity for iron, so that even without further conversion they are able to bind the iron as desired and to remove it from the body. Compared with the known compounds, the novel compounds of the present invention prove not only to be orally more effective, but also to be readily toler¬ able.

The present invention thus makes available compounds of the formula I which are distin¬ guished both by their outstanding oral activity and by their tolerability even at high dosage.

The invention relates preferably to compounds of the formula I, in which R¹ is hydrogen; R² is OR³ or NR⁴R⁵; R³ is unsubstituted or substituted lower alkyl, cyclo- lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or lower alkoxycar¬ boxy-lower alkyl; R⁴ and R⁵ independently of one another are hydrogen or unsubstituted or substituted lower alkyl; R⁶ and R⁷ are hydrogen; R⁸ and R⁹ individually are hydrogen or to¬ gether are n-butylene; and salts thereof.

Primarily, the invention relates to compounds of the formula i, in which R¹ is hydrogen; R² is OR³; R³ is unsubstituted or substituted lower alkyl, cyclo-lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or lower alkoxycarboxy-lower alkyl; R⁶ and R⁷ are hydrogen; R⁸ and R⁹ are hydrogen; and pharmaceutically acceptable salts thereof.

Especially, the invention relates to the compounds of the formula I, in which R¹ is hydrogen; R² is OR³; R³ is unsubstituted or substituted lower alkyl, cyclo-lower alkyl, lower alkoxy-lower alkyl or lower alkoxycarbonyl-lower alkyl; R⁶ and R⁷ are hydrogen; R⁸ and R⁹ are hydrogen; and pharmaceutically acceptable salts thereof.

The invention relates in particular to the compounds of the formula I, selected from the group consisting of

((2-hydroxybenzyl)-{2-[(2-hydroxybenzyl)methoxycarbonylmethylamino]ethyl}amino)acetic acid,

((2-hydroxybenzyl)-{2-[(2-hydroxybenzyl)ethoxycarbonylmethylamino]ethyl}amino)acetic acid,

[(2-[(1-acetoxy-2-methylpropoxycarbonylmethyl)-(2-hydroxybenzyl)amino]ethyl}-(2-hydroxy- benzyl)amino]acetic acid, and pharmaceutically acceptable salts thereof.

The invention especially relates to the specific compounds of the formula I and their salts described in the examples, in particular their pharmaceutically acceptable salts.

The compounds can be prepared in a manner known per se, by

a) hydrolysing a compound of the formula II

in which R', R , R , R , R and R are as defined under formula I and X is a leaving group, or

b) reacting a compound of the formula

in which R , R , R , R , R and X are as defined under formula II, with a compound of the formula Ilia

R²-H <»^la) in which R² is as defined under formula I, or

c) reacting a compound of the formula IV

in which R\ R , R , R and R are as defined under formula I, with a compound of the for¬ mula IVa

_R ³_γ (IVa)

in which R³ is as defined under formula I and Y is halogen,

it being possible, if appropriate, for substituents in protected form tc be present, and then converting this compound, if necessary, into a compound of the fornula I by removal of protective groups, and, if desired, converting a compound of the foτnula I into another compound of the formula I, and/or, if desired, converting a salt obtained into the free com¬ pound or into another salt, and/or, if desired, converting a free compound of the formula I obtained having salt-forming properties into a salt.

In the following more detailed description of the processes, the symbols R¹ - R⁹, X and Y are each as defined under formulae I to IVa, if not stated otherwise

Process (a): The reaction according to process (a) corresponds to the controlled partial hydrolysis, which is known per se, of a derivative of a difunctional cέvhoxylic acid. X here can be, for example, alkoxy or ammo, alkylamino or dialkylammo, but also halogen, O-acyl, heteroanalogous O-acyl, activated amide or activated ester. The hydrolysis is carried out in a solvent or solvent mixture, advantageously in the presence of at least half an equivalent of water, preferably with base or acid catalysis. The reaction takes place with cooling, at ambient temperature or at elevated temperature up to the boiling point of the reaction mixture. In a particularly preferred embodiment, a symmetrical diester of the formula V

is partially hydrolysed in the presence of approximately one mole equivalent of a base, preferably of an aqueous alkali metal hydroxide solution, in particular sodium hydroxide so¬ lution, at elevated temperature.

Process b) The reaction according to process b) corresponds to the reaction of a carboxylic acid or of a reactive carboxylic acid derivative, which is known per se, with an alcohol or amine X here can be, for example, hydroxyl, halogen, O-acyl, heteroanalogous O-acyl, ac¬ tivated amide or activated ester. The reaction can be carried out with or without solvent and take place with cooling, at ambient temperature or at elevated temperature up to the boiling point of the reaction mixture The reaction can be promoted, if appropriate, by catalysis. Ad¬ vantageously, the reaction conditions are selected such that one of the reaction products can be continuously removed from the reaction mixture, for example by precipitation or dis¬ tillation

Carboxylic acids are converted, for example, into a reactive derivative by converting them, for example, into a corresponding ester, which may be activated, a corresponding activated amide, acid halide, e.g. a chloride or bromide, carboxylic anhydride, mixed anhydride, for example with other carboxylic acids, such as pivahc acid or tπchloroacetic acid, hemiesters, in particular carbonic acid hemiesters, such as the ethyl- or isobutylcarbonic acid hemi¬ esters, or organic sulfonic acids, such as p-toluenesulfonic acid, nitrile or azide. Activated esters are, for example, esters with vinylogous alcohols (i.e. enols, such as vinylogous lower alkenols), haloiminomethyl esters, such as chlorodimethyhminomethyl esters (prepared from the carboxylic acid and, for example, dιmethyl-(1-chloroethylιdene)ιmιnιum chloride), or aryl esters, such as suitably substituted phenyl esters, e.g. phenyl esters sub¬ stituted by halogen and/or nitro, for example 4-nitrophenyl esters, 2,3-dinitrophenyl esters or 2,3,4,5,6-pentachlorophenyl esters, N-heteroaromatic esters, such as n-benzotriazole es¬ ters, e.g. 1 -benzotriazole ester, or N-diacylimino esters, such as N-succinylimino- or N-phthalimino esters. Suitable activated amides which may be mentioned by way of exam¬ ple are imidazolides, 1 ,2,4-triazolides, tetrazolides or 1 ,2,4-oxadiazolinonides.

In a preferred embodiment of the process, the conversion is carried out, preferably in situ, into a reactive intermediate with the aid of condensation reagents. Condensing reagents are, for example, carbodiimides, such as N,N'-diethyl-, N,N'-dipropyl-, N.N'-dicyclohexyl- or N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, 1 ,2-oxazolium compounds, for example 2-ethyl-5-phenyl-1 ,2-oxazolium-3'-sulfonate or 2-tert-butyl-5-methylisoxazolium perchlorate, suitable acylamino compounds, for example 2-ethoxy-1-ethoxycarbonyl-1 ,2-dihydro- quinoline, diethylphosphoryl azide or diphenylphosphoryl azide, preferably diphenyl cyano- phosphonate, diethyl cyanophosphonate, 1-chloro-N,N,2-trimethylpropenylamine, carbonyl compounds, such as N,N-carbonyldiimidazole.

Process c): Process c) corresponds to the reaction of carboxylic acid anions with halides, which is known per se. The reaction can be carried out with or without solvent, with cooling, at ambient temperature or at elevated temperature up to the boiling point of the reaction mixture. Advantageously, it is carried out in an inert polar solvent at elevated temperature.

The starting compounds of the formulae II, III and IV are known or can easily be prepared by known processes from HBED or HBED derivatives which are simple to prepare. HBED can be prepared, for example, by the process disclosed in US 3,632,637.

Protective groups, their introduction and removal are described, for example, in J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London, New York 1973, and in "Methoden der organischen Chemie" [Methods of organic chemistry], Houben-Weyl, 4th Edition, Vol. 1571 , Georg-Thieme-Veriag, Stuttgart 1974, and also in Theodora W. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York 1981. It is characteristic of protective groups that they can be removed easily, i.e. without undesired side reactions taking place, e.g. solvolytically, reductively, photolytically or alternatively under physiological conditions. Hydroxyl groups can be present, for example, in the form of an easily cleavable ester or ether group, preferably of an alkanoyl or aralkanoyl ester group or of a cycloheteroalkyl, aralkyl or alkoxyalkyl ether group, but also of a silyl ester or silyl ether group, in particular as an acetyl or benzoyl ester or as a tetrahydropyranyl, benzyl or methoxymethyl ether.

The protective groups which are not a constituent of the desired final product of the for¬ mula I are removed in a manner known per se, e.g. by means of solvolysis, in particular hy¬ drolysis, alcoholysis or acidolysis, or by means of reduction, optionally stepwise or simulta¬ neously.

Compounds of the formula I can also be converted into other compounds of the formula I

When starting compounds of the formula I or any intermediates contain interfering reactive groups, e.g. carboxyl, hydroxyl or ammo groups, these can be temporarily protected by eas¬ ily removable protective groups.

To work up the compounds of the formula I obtainable or their salts and, if necessary, the intermediates, customary processes are used, for example solvolysis of excess reagents; recrystallization, chromatography, e.g. partition, ion or gel chromatography, partition be¬ tween an inorganic and organic solvent phase; single or multiple extraction, in particular af¬ ter acidification or increasing the basicity or the salt content, drying over hygroscopic salts or at elevated temperature, if desired with passing through or passing by of a gas stream; digestion, filtration; washing; dissolution; evaporation (if necessary in a vacuum or high vac¬ uum); distillation; precipitation; centrifugation; crystallization, for example of compounds obtained in oil form or from the mother liquor, it also being possible to seed the final product with a crystal; lyophihzation; or a combination of two or more of the working-up steps men¬ tioned, which can also be employed repeatedly; etc.

Starting materials and intermediates can be used in pure form, for example after working up, as last-mentioned, in partially purified form or alternatively, for example, directly as crude products. The compounds, including their salts, can also be obtained in the form of hydrates or sol- vates, or their crystals can include, for example, the solvent used for crystallization.

Solvents and diluents are, for example, water, alcohols, e.g. lower alkanols, such as methanol, ethanol, propanol or butanol, diols, such as ethylene glycol, tri- or polyols, such as glycerol or diethylene glycol, or aryl alcohols, such as phenol or benzyl alcohol, acid amides, e.g. carboxamides, such as N,N-dimβthylformamide, or N,N-dimethylacetamide, amides of inorganic acids, such as hexamethylphosphoramide, ethers, e.g. cyclic ethers, such as tetrahydrofuran or dioxane, or acyclic ethers, such as diethyl ether or ethylene glycol dimethyl ether, halogenated hydrocarbons, such as halo-lower alkanes, e.g. methylene chloride or chloroform, ketones, such as acetone, nitriles, such as acetonitrile, esters, such as ethyl acetates, bisalkane sulfoxides, such as dimethyl sulfoxide, nitrogen heterocycies, such as N-methylpyrrolidone or pyridine, hydrocarbons, e.g. lower alkanes, such as hexane or heptane, or aromatics, such as benzene, toluene or xylene(s), or mixtures of these solvents, it being possible for the suitable solvents in each case for the abovementioned reactions and working-up steps to be selected.

In the process of the present invention, those starting substances and intermediates, in each case in free form or in salt form, are preferably used which lead to the compounds I or their salts described as particularly valuable at the outset. Novel starting substances and intermediates, in each case in free form or in salt form, for the preparation of the com¬ pounds I or their salts, their use and processes for their preparation also form a subject of the invention.

The invention also relates to those embodiments of the process in which a compound ob¬ tainable in any desired process stage as an intermediate is used as a starting material and the missing process steps are carried out, or in which a starting substance is formed under the reaction conditions or is used in the form of a derivative, e.g. of a salt thereof.

Salts of compounds I can be prepared in a manner known per se. Thus acid addition salts, for example, of compounds I are obtained by treatment with a suitable acid or a suitable ion-exchange reagent and salts with bases are obtained by treatment with a suitable base or a suitable ion-exchange reagent. Salts of compounds of the formula I can be converted in a customary manner into the free compounds I; acid addition salts can be converted, for example, by treatment with a suitable basic agent or a suitable ion-exchange reagent; and salts with bases can be converted, for example, by treatment with a suitable acid or a suit¬ able ion-exchange reagent.

Salts of compounds I can be converted into other salts of compounds I in a manner known per se; acid addition salts can be converted, for example, into other acid addition salts, e.g. by treatment of a salt of an inorganic acid, such as a hydrochloride, with a suitable metal salt, such as a sodium, barium or silver salt, of an acid, e.g. silver acetate, in a suitable sol¬ vent, in which an inorganic salt formed, e.g. silver chloride, is insoluble and thus precipitates from the reaction mixture.

Depending on the procedure or reaction conditions, the compounds I with salt-forming properties can be obtained in free form or in the form of salts.

As a result of the close relationship between the compound I in free form and in the form of its salts, in what has been said above and what follows the free compound I or its salts are, if appropriate, to be understood analogously and expediently as also meaning the corre¬ sponding salts or the free compound I.

The compounds I including their salts of salt-forming compounds can also be obtained in the form of their hydrates and/or include other solvents, for example, if appropriate, solvents used for the crystallization of compounds present in solid form.

The compounds I and their salts, depending on the choice of the starting substances and working procedures, can be present in the form of one of the possible isomers, for example stereoisomers or tautomers, or as a mixture thereof. In this context, pure isomers obtainable are, for example, pure enantiomers, pure diastereomers or pure tautomers. Correspond¬ ingly, isomer mixtures which can be present are, for example, racemates or diastereoisomer mixtures. Isomer mixtures of compounds I in free form or in salt form obtainable according to the process or in other way can be separated into the components in a customary man¬ ner, e.g. on the basis of the physicochemical differences of the constituents, in a known manner by fractional crystallization, distillation and/or chromatography. Advantageously, the more active isomer is isolated. The invention likewise relates to the use of the compounds I and their pharmaceutically ac¬ ceptable salts for the treatment of illnesses which cause an excess of iron in the human or animal body or are caused by it, preferably in the form of pharmaceutically acceptable preparations, in particular in a method for the therapeutic treatment of the human body, and to such a method of treatment.

The invention likewise relates to pharmaceutical preparations which contain a compound I or a pharmaceutically acceptable salt thereof as active compound, and to processes for their preparation. These pharmaceutical preparations are those for enteral, in particular oral, and furthermore rectal, administration and those for parenteral administration to warm¬ blooded animals, especially to man, the pharmacological active compound being contained on its own or together with customary pharmaceutical adjuncts. The pharmaceutical prepa¬ rations contain (in per cent by weight), for example, from approximately 0.001 % to 100 %, preferably from approximately 0.1 % to approximately 50 %, of the active compound.

Pharmaceutical preparations for enteral or parenteral administration are, for example, those in unit dose forms, such as sugar-coated tablets, tablets, capsules, suspendable powders, suspensions or suppositories, or ampoules. These are prepared in a manner known per se, e.g. by means of conventional pan-coating, mixing, granulation or lyophilization processes. Pharmaceutical preparations for oral administration can thus be obtained by combining the active compound with solid carriers, if desired granulating a mixture obtained and proces¬ sing the mixture or granules, if desired or necessary, after addition of suitable adjuncts to give tablets or sugar-coated tablet cores.

Suitable carriers are, in particular, fillers such as sugars, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or cal¬ cium hydrogen phosphate, furthermore binders, such as starch pastes, using, for example, maize, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyr¬ rolidone, and, if desired, disintegrants, such as the abovementioned starches, furthermore carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. Adjuncts are primarily flow-regulating and lubricating agents, e.g. salicylic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Sugar-coated tablet cores are provided with suitable, if desired enteπc, coatings, using, inter aha, concentrated sugar solutions which, if desired, contain gum arab_le, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colorants or pigments, e.g. for the identification or the marking of various doses of active compound, can be added to the tablets or sugar- coated tablet coatings

Further orally administerable pharmaceutical preparations are hard gelatin capsules and also soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The hard gelatin capsules can contain the active compound in the form of granules, e.g. as a mixture with fillers, such as lactose, binders, such as starches, and/or ghdants, such as talc or mag¬ nesium stearate, and, if desired, stabilizers. In soft capsules, the active compound is pref¬ erably dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols, it also being possible to add stabilizers.

Moreover, suspendable powders, e.g. those which are described as "powder in bottle", ab¬ breviated "PIB", or ready-to-dnnk suspensions, are suitable for an oral administration form. For this form, the active compound is mixed, for example, with pharmaceutically acceptable surface-active substances, such as, for example, sodium lauryl sulfate or polysorbate, sus¬ pending auxiliaries, e.g. hydroxypropylcellulose, hydroxypropylmethylcellulose or another known from the prior art and previously described, for example, in "Handbook of Pharma¬ ceutical carriers", pH regulators, such as citric or tartaric acid and their salts or a USP buffer and, if desired, fillers, e.g. lactose, and further auxiliaries, and dispensed into suitable ves¬ sels, advantageously single-dose bottles or ampoules. Immediately before use, a specific amount of water is added and the suspension is prepared by shaking. Alternatively, the water can also be added even before dispensing.

Rectally administrable pharmaceutical preparations are, for example, suppositories which consist of a combination of the active compound with a suppository base. A suitable sup¬ pository base is, for example, natural or synthetic triglycerides, paraffin hydrocarbons, poly¬ ethylene glycols or higher alkanols. Gelatin rectal capsules can also be used which contain a combination of the active compound with a base substance. Possible base substances are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons. For parenteral administration, aqueous solutions of an active compound in water-soluble form, e.g. of a water-soluble salt, are primarily suitable; furthermore suspensions of the ac¬ tive compound, such as appropriate oily injection solutions, suitable lipophilic solvents or vehicles, such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, being used, or aqueous injection suspensions which contain viscosity-in¬ creasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, also stabilizers.

The dosage of the active ingredient can depend on various factors, such as activity and du¬ ration of action of the active compound, severity of the illness to be treated or its symptoms, manner of administration, warm-blooded animal species, sex, age, weight and/or individual condition of the warm-blooded animal. The doses to be administered daily in the case of oral administration are between 10 and approximately 120 mg/kg, in particular 20 and ap¬ proximately 80 mg/kg, and for a warm-blooded animal having a body weight of approxi¬ mately 40 kg, preferably between approximately 400 mg and approximately 4,800 mg, in particular approximately 800 mg to 3,200 mg, which is expediently divided into 2 to 12 indi¬ vidual doses.

The following examples are intended to illustrate the invention described above, but without restricting it to them. (Above and below, the following abbreviations - if not stated otherwise - are used: HBED = N,N'-di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (= [{2-[carboxymethyl-(2-hydroxybenzyl)amino]ethyl}-(2-hydroxybenzyl)amino]acetic acid), m.p. = melting point, dec. = decomposition, HPLC = high performance liquid chromato¬ graphy, TLC = thin-layer chromatography).

HPLC conditions: column, NUCLEOSIL^® 5 C18 L, 4.6 mm / 25 cm; eluent, water/aceto- nitrile/0.1 % trifluoroacetic acid; gradient, the initial content of acetonitrile of 20 % is in¬ creased linearly to 100 % in the course of 11 minutes and then kept at 100 % for a further 5 minutes; pressure, 80-130 bar; flow rate, 1 ml/min; temp., 30°C; detection, 215 nm. Example 1 : Sodium ((2-hvdroxybenzylW2-r(2-hvdroxybenzyl)methoxycarbonylmethylamιno1- ethyl)amιno)acetate

Methyl ((2-hydroxybenzyl)-{2-[(2-hydroxybenzyl)methoxycarbonylmethylamιno]ethyl}amιno) acetate (3.4 g, 8.16 mmol) is dissolved in methanol (80 ml) and treated with 2 M sodium hydroxide solution (4.1 ml). The clear solution is stirred at 50 °C for 18 hours. The resulting colourless suspension is cooled in an ice bath and stirred at 0^CC for a further 4 hours. The resulting crystals are filtered off, washed with cold methanol, sucked dry and dried at 50°C in a high vacuum. The title compound is obtained as colourless crystals. M.p. 211 -213°C (dec), HPLC: t_R = 8.17 mm.

The starting material can be prepared from HBED, for example, as follows:

a) Methyl ((2-hydroxybenzylH2-r(2-hvdroxybenzyl)methoxycaιt)onylmethylamιno1ethyl)- aminoϊacetate: (CG. Pitt, Y. Bao, J. Thompson, M.C Wani, H. Rosenkrantz, J. Metterville, J. Med. Chem. 29, 1231 (1986)) HBED (5 g, 10.05 mmol) is dissolved in methanol (50 ml). Thionyl chloride (6.5 ml, 90.3 mmol) is added dropwise to the mixture with ice-cooling. After completion of the addition of thionyl chloride, the ice bath is removed and the resulting solu¬ tion is heated to 60 ^CC for 3 hours. The mixture is then stirred at room temperature over¬ night and subsequently evaporated. The residue is taken up in ethyl acetate and the mix¬ ture is treated with saturated sodium hydrogencarbonate solution. The organic phase is separated, washed with brine, dried over magnesium sulfate and evaporated. The residual oil is purified by flash chromatography. A pale yellow oil is obtained, which on standing so¬ lidifies to give a colourless crystalline mass. M.p. 91-92 °C, TLC. R,=0.59 (ethyl acetate/ hexane 1 :1), HPLC: t_R=9.87 mm.

Example 2: Sodium (⁽2-hvdroxybenzylH2-r⁽2-hvdroxybenzvnethoxycarbonylmethylamιnol- ethyllaminolacetate

Ethyl[{2-[ethoxycarbonylmethyl-(2-hydroxybenzyl)amιno]ethyl}-(2-hydroxybenzyl)amιno]- acetate (111.1 g, 0.25 mol) is dissolved in ethanol (1.8 I) heated to 40 °C and the solution is treated with 2M sodium hydroxide solution (125 ml, 0.25 mol). The mixture is then stirred at 40°C for 18 hours. The resulting suspension is then cooled in an ice bath. The precipitated product is filtered off, washed with cold methanol, sucked dry and dried at 60 °C in a high vacuum. The product is obtained as a voluminous colourless powder. M.p. 182-185°C (dec), HPLC: t_R = 10.12 mm. The starting material can be prepared from HBED, for example, as follows

a) Ethyl ((2-hvdroxybenzyl)-(2-[(2-hvdroxybenzvπethoxycarbonylmethylamιno1ethyl)amιno)- acetate: (CG. Pitt, Y. Bao, J Thompson, M.C. Wani, H. Rosenkrantz, J Metterville, J. Med Chem. 29, 1231 (1986)) HBED hydrochloπde dihydrate (50 g, 93.07 mmol) is initially intro¬ duced into ethanol (100 ml). A moderate stream of hydrogen chloride is passed into the re¬ sulting suspension for 30 mm In the course of this, the internal temperature is kept between 20 and 25 °C by ice-cooling After the introduction of gas is complete, the mixture is stirred at 50 °C for 20 hours. The reaction solution cooled to room temperature is concentrated on a rotary evaporator and the residue is taken up in methyl tert-butyl ether. The product can be crystallized by addition of hexane. A final recrystallization from boiling ethanol yields the title compound as colourless glistening crystals. M.p. 77-78 °C, TLC R,=0.27 (ethyl acetate / hexane 1 :2) , HPLC: t_R = 10.81 mm.

Example 3: ((2-Hvdroxybenzyl)-(2-r(2-hvdroxybenzyl)ethoxycarbonylmethylamιnolethyl}- aminolacetic acid

Modification A (free of water of crystallization, cryst from dichloromethane) Sodium ((2-hydroxybenzyl)-{2-[(2-hydroxybenzyl)ethoxycarbonylmethylamιno]ethyl}ammo)acetate (Example 2, 5 2 g, 12 mmol) is suspended in ethanol (100 ml) and treated with glacial acetic acid (2 ml) After stirring at room temperature for 2 hours, almost everything has gone into solution The mixture is evaporated to dryness and the residue is digested with dichloro¬ methane (100 ml) and filtered The product crystallizes from the filtrate in the form of a pale pink-coloured powder m.p. 160-165 °C (dec), TLC. R_f=0.40 (dichloromethane/ metha- nol/glacial acetic acid 9-1 :0 05), HPLC. t_R = 9.49 mm

Modification B- (monohydrate, crystallized from ethanol) Sodium ((2-hydroxybenzyl)- {2-[(2-hydroxybenzyl)ethoxycarbonylmethylamιno]ethyl}amιno)acetate (Example 2, 4.38 g, 10 mmol) is suspended in ethanol (250 ml) and treated in one portion with 2 M hydrochloric acid (5 ml, 10 mmol). The resulting suspension is stirred at room temperature for two hours. The crude product is then filtered off, dissolved again in boiling ethanol (250 ml) and sub¬ jected to clarifying filtration On cooling the filtrate, the product precipitates in the form of fine colourless crystals: m.p 130-132 ^CC (dec), TLC. R_f=0.18 (dichloromethane/methanol/ water/glacial acetic acid 9:1 :0.1:0.05), HPLC: t_R = 9.47 mm. Modif ication C: (dihydrate, crystallized from water) Sodium ((2-hydroxybenzyl)- {2-[(2-hydroxybenzyl)ethoxycarbonylmethylamino]ethyl}amino)acetate (Example 2, 10 g, 22.8 mmol) is dissolved in warm water (350 ml) at 30 °C, which has previously been treated with 4 M hydrochloric acid (25 ml, 100 mmol). After everything has gone into solution, the mixture which has again been cooled to room temperature is slowly treated with 4 M sodium hydroxide solution (15 ml, 60 mmol) and is slowly stirred mechanically overnight. During this time, the product precipitates as a colourless thick slurry. The crystals are filtered off, washed with ice water until neutral, sucked dry and dried in vacuo at 50°C: colourless mi- crocrystaliine powder, m.p. 93-98 °C (dec, a slow phase transition to modification B takes place from 55 °C with release of water: on slow heating it is not possible to observe the low melting point of modification C, but the crystals melt at the melting point of 130 ^CC typical of modification B), TLC: R_f=0.18 (dichloromethane/methanol/water/glacial acetic acid 9:1 :0.1 :0.05), HPLC: t_R = 9.41 min. A second crystal fraction can be obtained from the mother liquor by addition of 4 M sodium hydroxide solution (10 ml, 40 mmol).

Example 4: Potassium ((2-hvdroxybeπzylM2-f(2-hvdroxybenzyltethoxycarbonylmethyl- aminolethyl)amino)acetate

Finely powdered ethyl ((2-hydroxybenzyl)-{2-[(2-hydroxybenzyl)ethoxycarbonylmethyl- amιno]ethyl}amino)acetate (Example 2a, 10 g, 22.5 mmol) is suspended in ethanol (150 ml) and treated with a solution of potassium hydroxide pellets 85% (1.49 g, 22.5 mmol) in water (10 ml). The mixture is stirred at 40 °C for 14 hours. The suspension is filtered warm and the filter residue is washed with a little ethanol. The combined filtrates are evaporated. The crude product which remains in the form of a viscous foamy resin is purified further by re¬ crystallization from ethanol / terf-butyl methyl ether. The crystals obtained in this way are dried at 80°C in a high vacuum: almost colourless microcrystalline powder: m.p. 185-187 °C (dec), HPLC: t_R = 9.47 min.

Example 5: ((2-HvdroxybenzylH2-f(2-hvdroxybenzyl)ethoxycarbonylmethylaminolethyll- amino)acetic acid, salt with methane sulfonic acid

((2-Hydroxybenzyl)-{2-[(2-hydroxybenzyl)ethoxycarbonylmethylamino]ethyl}amino)acetic acid (Example 3, 2.5 g, 6 mmol) is dissolved in warm ethanol (100 ml). After the mixture has cooled to room temperature, a solution of methanesulfonic acid (0.39 ml, 6 mmol) in ethanol (5 ml) is added dropwise. The clear solution obtained is evaporated on a rotary evaporator. The residual viscous syrup can be crystallized in ethanol / ferf-butyl methyl ether. The crys- tals obtained are filtered off with suction, washed with a little terf-butyl methyl ether, sucked dry and dried to constant weight at 100 °C in a high vacuum. Colourless crystals, m.p. 179- 182°C, HPLC: t_R = 8.66.

Example 6: ((2-Hvdroxybenzyl)-(2-fι2-hvdroxybenzyl)propoxycarbonylmethylamino]ethyl}- aminotøcetic acid

A suspension of propyl ((2-hydroxybenzyl)-{2-[(2-hydroxybenzyl)propoxycarbonylmethyl- amino]ethyl}amino)acetate (2.3 g , 4.87 mmol) in n-propanol (30 ml) is stirred at 40 °C until everything has dissolved. 2 M sodium hydroxide solution (2.4 ml, 4.8 mmol) is then added in one portion and the mixture is additionally stirred overnight at an internal temperature of 40°O The resulting suspension is cooled in an ice bath and filtered. The filter residue is washed with cold n-propanol and sucked dry. For purification, the crude product is taken up in dichloromethane (180 ml) and treated with glacial acetic acid (1.5 ml). The mixture is stirred at room temperature for 2 hours and then evaporated. The residue is flash-chromato- graphed (eluent: dichloromethane/methanol/glacial acetic acid 90:10:0.5). An analytically pure preparation is finally obtained by recrystallization from dichloromethane/hexane: pale pink crystals, m.p. 110 -115 °C, TLC: R_t=0.42 (dichloromethane/methanol/glacial acetic acid 90:10:0.05), HPLC: t_R = 10.03 min.

a) Propyl ((2-hvdroxybenzyl)-{2-[(2-hvdroxybenzvQpropoxycarbonylmethylaminolethyl}- amino)acetate: Preparation analogously to Example 2a: mixture: HBED hydrochloride dihy- drate (5 g, 9.31 mmol), n-propanol (70 ml). Colourless crystals, m.p. 63 - 65 °C (methyl terf- butyl ether / hexane) , TLC: R,=0.77 (2% methanol in dichloromethane), HPLC: t_R = 11.81 min.

Example 7: ((2-Hvdroxybenzyl)-{2-f(2-hvdroxybenzyl)isopropoxycarbonylmethylaminolethyl}- amino)acetic acid

Preparation analogously to Example 6, mixture: propyl ((2-hydroxybenzyl)-{2-[(2-hydroxy- benzyl)isopropoxycarbonylmethylamino]ethyl)amino)acetate (2.3g , 4.87 mmol), isopropanol (30 ml), 2 M sodium hydroxide solution (4.8 ml, 9.6 mmol). Purification by flash chromatog¬ raphy (eluent: dichloromethane/methanol/glacial acetic acid 9:1:0.05) and recrystallization from dichloromethane/hexane. Pink-coloured crystalline powder, m.p. 129-132°C, TLC: R_f=0.33 (dichloromethane/methanol/glacial acetic acid 9:1 :0.05), HPLC: t_R=10.01 min. aUsopropyl (.2-hvdroxybeπzyl)-f2-f(2-hvdroxybenzyl)isopropoxycarbonylmethylaminolethyl)- aminotøcetate (CG. Pitt, Y. Bao, J. Thompson, M.C. Wani, H. Rosenkrantz, J. Metterville, J. Med. Chem. 29, 1231 (1986)) Preparation analogously to Example 2a: mixture: HBED hy- drochloride dihydrate (5 g, 9.31 mmol), isopropanol (70 ml). Purification by flash chromatog¬ raphy (2% methanol in dichloromethane). Almost colourless oil, TLC: R_f=0.76 (2% methanol in dichloromethane), HPLC: t_R = 11.82 min

Example 8: ((2-HvdroxybenzylV(2-r(2-hvdroxybenzyl)butoxycarbonylmethylamino1ethvπ- amino)acetic acid

Preparation analogously to Example 6, mixture: butyl ((2-hydroxybenzyl)-{2-[(2-hydroxy- benzyl)butoxycarbonylmethylamino]ethyl}amino)acetate (2.3g, 4.59 mmol), 1-butanol (30 ml), 2 M sodium hydroxide solution (2.3 ml, 4.6 mmol). Purification by flash chromatog¬ raphy (dichloromethane/methanol/glacial acetic acid 9:1 :0.05) and recrystallization from di¬ chloromethane/hexane. Pink-coloured crystals, m.p. 127-130°C, TLC: R_f=0.25 (dichloro- methane/methanol/glacial acetic acid 9:1 :0.05), HPLC: t_R=11.19 min.

a) Butyl ((2-hvdroxybenzyll-(2-[f2-hvdroxybenzvπbutoxycarbonylmethylaminolethyl)amino)- acetate: Preparation analogously to Example 2a, mixture: HBED hydrochloride dihydrate (5 g, 9.31 mmol), 1-butanol (70 ml). Purification by flash chromatography (methyl terf-butyl ether/hexane 1 :2) and recrystallization from a little methyl terf-butyl ether/hexane. Colour¬ less crystals, m.p. 58-60 °C, TLC: R,=0.79 (2% methanol in dichloromethane), HPLC: t_R=12.70 min.

Example 9: ((2-HvdroxybenzylH2-ff2-hvdroxybenzvmsobutoxycarbonylmethylamino1ethyll- amino)acetic acid

Preparation analogously to Example 6, mixture: isobutyl ((2-hydroxybenzyl)-{2-[(2-hydroxy- benzyl)-isobutoxycarbonylmethylamino]ethyl}amino)acetate (2.5g, 5 mmol), isobutanol (30 ml), 2 M sodium hydroxide solution (2.5 ml, 5 mmol). Purification by flash chromatogra¬ phy (dichloromethane/methanol/glacial acetic acid 9:1 :0.05) and recrystallization from di¬ chloromethane/hexane. Pink-coloured crystals, m.p. 145-149°C, TLC: R_t=0.32 (dichloro- methane/methanol/glacial acetic acid 9:1 :0.05), HPLC: t_R=10.58 min.

a) Isobutyl ι2-hvdroxybenzylH2-f(2-hvdroxybenzvπisobutoxycarbonylmethylamino]ethvO- amino)acetate: Preparation analogously to Example 2a, mixture: HBED hydrochloride dihy- drate (5 g, 9.31 mmol), isobutanol (70 ml). Purification by flash chromatography (methanol/ dichloromethane 2:98) and recrystallization from methyl terf-butyl ether/hexane. Colourless crystals, m.p. 89-92 °C, TLC: R_t=0.26 (1% methanol in dichloromethane), HPLC: t_R=12.56 min.

Example 10: Sodium ((2-hvdroxybenzyl)-(2-f(2-hvdroxybenzvh-1-pentoxycarbonylmethyl- aminolethyllaminoϊacetate

Preparation analogously to Example 2, mixture: pentyl ((2-hydroxybenzyl)-{2-[(2-hydroxy- benzyl)pentoxycarbonylmethylamino]ethyl}amino)acetate (2.5g, 4.73 mmol), 1 -pentanol (30 ml), 2 M sodium hydroxide solution (2.4 ml, 4.8 mmol). Purification by washing with cold pentanol. Colourless crystals, m.p. 170-173°C, TLC: R,=0.37 (dichloromethane/methanol/ glacial acetic acid 9:1:0.05), HPLC: t_R=11.14 min.

a) Pentyl (2-hvdroxybenzyl)-{2-f(2-hvdroxybenzyl)pentoxycarbonylmethylamino1ethyll- aminoϊacetate (CG. Pitt, Y. Bao, J. Thompson, M.C. Wani, H. Rosenkrantz, J. Metterville, J. Med. Chem. 29, 1231 (1986)) Preparation analogously to Example 2a, mixture: HBED hy¬ drochloride dihydrate (5 g, 9.31 mmol), 1-pentanol (70 ml). Purification by flash chromatog¬ raphy (methanol/dichloromethane 1 :99) and recrystallization from methyl terf-butyl ether/ hexane. Colourless crystals, m.p. 73-75 °C, TLC: R,=0.43 (1% methanol in dichloro¬ methane), HPLC: t_R=13.25 min.

Example 11 : Sodium f(2-fisopropoxycarbonylmethyl-(2-hvdroxy-benzyl)aminolethyl}- (2-hvdroxybenzyl)amino]acetate

A moderate stream of hydrogen chloride is passed at room temperature for,10 minutes into a mixture of dichloromethane (12 ml) and tetrahydrofuran (12 ml). The mixture is then cooled to 0 °C in an ice bath and a solution of [{2-[isopropoxycarbonylmethyl-(2-meth- oxymethoxy-benzyl)amino]ethyl}-(2-methoxymethoxybenzyl)amino]acetic acid (2 g, 3.85 mmol) in dichloromethane (10 ml) is added dropwise such that the internal temperature does not rise above 5°O After completion of the addition, the mixture is stirred at room temperature overnight. The resulting red solution is evaporated in a rotary evaporator and the residue is treated with dichloromethane (50 ml) and sat. sodium hydrogencarbonate solution (50 ml) and extracted. The aqueous phase is reextracted once with dichloro¬ methane. The combined organic phases are washed with brine, dried over sodium sulfate, filtered off and evaporated. The crystalline residue is triturated with warm dichloromethane and then dried at room temperature in a high vacuum. The title compound is obtained in the form of an almost colourless powder: 183-185 °C (dec), HPLC: t_R=9.81 mm.

Preparation of the starting compound: a^ Ethyl r(2-fethoxycarbonylmethyl-(2-methoxymethoxybenzyl)amιnolethyl)-(2-methoxymeth- oxybenzvDaminolacetate: A solution of ethyl ((2-hydroxybenzyl)-{2-[(2-hydroxybenzyl)-eth- oxycarbonylmethylamιno]ethyl}amιno)acetate (Example 2a, 1.1 l g, 2.5 mmol) in tetrahydro¬ furan (20 ml) is cooled to 0°C in an ice bath and treated in one portion with sodium ethoxide (375 mg, 5.5 mmol). A yellow-coloured slightly cloudy solution is formed, which is addition¬ ally stirred at 0°C for a further 30 mm. A solution of bromomethyl ether 90% (656 mg, 0 48 ml, 5.25 mmol) in tetrahydrofuran (5 ml) is then added dropwise such that the internal tem¬ perature does not rise above 5 °C A finely crystalline colourless precipitate immediately separates. After the suspension has been stirred at 0°C for 2 hours, the mixture is poured onto a mixture of ether and saturated sodium hydrogencarboπate solution. The organic phase is separated off and the aqueous phase is extracted twice with ether. The combined extracts are washed (3χ water, 1 x brine), dried (sodium sulfate) and evaporated. The prod¬ uct is obtained as a pale yellow oil: TLC: R_f=0.12 (ethyl acetate/hexane 1 -4), HPLC: t_R=12 31 mm

b) Disodium f(2-fcarboxycarbonylmethyl-(2-methoxymethoxybenzvhamιnolethyl)-(2-meth- oxymethoxybenzvDaminolacetate: Ethyl [{2-[ethoxycarbonylmethyl-(2-methoxymethoxy- benzyl)amιno]ethyl}-(2-methoxymethoxybenzyl)amιno]acetate (586.7 g, 1 mol) is taken up in ethanol (2 I) and treated with 2 M sodium hydroxide solution (1 1 I, 2.2 mol). The mixture is stirred at room temperature for 2 hours, the initial suspension changing into a red-brown solution after about 10 minutes The mixture is concentrated in vacuo, the residue is evapo¬ rated with toluene and ethanol and finally with acetone and a red-brown resin is obtained. The residue is dissolved in acetone (2 I) and crystallized overnight at -30 °C The mixture is diluted with ethyl acetate (500 ml), the crystals are filtered off on a suction filter and washed with acetone and the product is thus obtained as an orange powder. TLC: R_f=0.1 (dichloro- methane/methanol/conc ammonia 40:10:1), HPLC: t_R=9.68 mm.

c) f(2-rCarboxymethyl-(2-methoxymethoxybenzvhamιno1ethyl)-(2-methoxymethoxybenzyl)- ammolacetic acid: A solution of disodium [{2-[carboxycarbonylmethyl-(2-methoxymethoxy- benzyl)amιno]ethyl}-(2-methoxymethoxybenzyl)amιno]acetate (50 g, 96 mmol) in water (240 ml) is cooled to 0 °C in an ice bath 1 M hydrochloric acid (192 ml, 192 mmol) is then added dropwise such that the internal temperature does not rise above 5 °C After comple- tion of the addition, the mixture is stirred at 0 °C for a further 3 hours. The resulting thick suspension is treated with dichloromethane (500 ml) and vigorously stirred. The organic phase is isolated, dried over sodium sulfate, filtered and evaporated. The residual yellow foam is freed from solvent residues overnight at room temperature in a high vacuum. Pale yellow foam, TLC: (dichloromβthane/methanol/ammonia cone. 40:10:1), HPLC:t_R = 9.80 min.

ά) ri2-πsopropyloxycarbonylmethyl-(2-methoxymethoxybenzyl)aminolethyl>-(2-methoxy- methoxybenzvDaminolacetic acid: A solution of [{2-[carboxymethyl-(2-methoxymethoxy- benzyl)amino]ethyl}-(2-methoxymethoxybenzyl)amino]acetic acid (5,24 g, 11 mmol) in N,N- dimethylformamide (100 ml) is treated with caesium carbonate (1.79 g, 5.5 mmol). The re¬ sulting suspension is stirred at room temperature for one hour and is then treated in one portion with 2-bromopropane (2.06 ml, 22 mmol). The suspension, which is now yellow, is heated to 40°C and stirred at this temperature for 23 hours. After cooling, the solvent is re¬ moved in a high vacuum, the residue is taken up in dichloromethane (100 ml) and the mix¬ ture is treated with saturated sodium hydrogencarbonate solution (50 ml). The dichloro¬ methane phase is separated off, washed (1x brine), dried over sodium sulfate and evapo¬ rated. The residual resin is purified by flash chromatography (eluent: methanol/dichloro- methane 1 :9). The product is obtained as a yellowish syrup: TLC: R₍=0.20 (methanol/di- chloromethane 1 :9), HPLC: t_R=10.39 min.

Example 12: Sodium ff2-cvclopentyloxycarbonylmethyl-(2-hydroxybenzyl)amino1ethylH2- hvdroxybenzvOaminolacetate

Preparation analogously to Example 11, mixture: [{2-cyclopentyloxycarbonylmethyl-(2- methoxymethoxybenzyl)amino]ethyl}-(2-methoxymethoxybenzyl)amino]acetic acid (1.4 g, 2.57 mmol). The crude product is purified by digestion with ice-cold methanol and then dried at 80°C in a high vacuum: colourless crystals, m.p. 191-193°C (dec), TLC: R(=0.29 (methanol/dichloromethane 1 :9), HPLC: tR=10.55 min.

a) f(2-Cvclopentyloxycarbonylmethyl-(2-methoxymethoxybenzyl)amino]ethylH2-methoxy- methoxybenzvDaminolacetic acid: [{2-Carboxymethyl-(2-methoxymethoxy-benzyl)amino]- ethyl}-(2-methoxymethoxybenzyl)amino]acetic acid (Example 14c, 5.24g, 11 mmol), cy- clopentanol (1 ml, 11 mmol) and triphenylphosphine (2.97 g, 11 mmol) are initially intro¬ duced into tetrahydrofuran (200 ml). A solution of diisopropyl azodicarboxylate (2.12 ml, 11 mmol) is injected slowly into the solution, which has been pre-cooled in an ice bath, such that the internal temperature does not rise above 5°C Then the ice bath is removed and the solution is stirred overnight at room temperature. The clear yellow solution obtained is evaporated on a rotary evaporator. The oily residue is taken up in dichloromethane, washed (1x satd sodium hydrogencarbonate solution, 1x brine), dried over sodium sulfate, filtered and evaporated. The reaction product is isolated from the partially crystallizing residue by flash chromatography (eluent: methanol/dichloromethane 1 :9): yellow oil, TLC: (dichloromethane/methanol/conc ammonia 40:10:1 ), HPLC: t_R=9.80 min.

Example 13: (ι2-Hvdroxybenzyl)-(2-f(2-hvdroxybenzyl)-(2-methoxyethoxycarbonylmethyl)- amino1ethyllamino)acetic acid

Preparation analogously to Example 11 , mixture: [{2-[(2-methoxyethoxycarbonylmethyl)- (2-methoxymethoxybenzyl)amino]ethyl}-(2-methoxymethoxybenzyl)amino]acetic acid (2.1 g, 3.93 mmol). The crude product is recrystallized from dichloromethane/methyl terf-butyl ether and then dried at 80 °C in a high vacuum: almost colourless crystals, m.p. 156-159 °C, TLC: R,=0.26 (methanol/dichloromethane 1 :9), HPLC: t_R=9.17 min.

a) r(2-[(2-Methoxyethoxycarbonylmethyl)-(2-methoxymethoxybenzvπamino1ethyl)-(2-meth- oxymethoxybenzvPaminolacetic acid: Preparation analogously to Example 12a, mixture: [{2- [carboxymethyl-(2-methoxymethoxybenzyl)amino]ethyl}-(2-methoxymethoxy-benzyl)amino]- acetic acid (Example 14c, 5.24g, 11 mmol), ethylene glycol monomethyl ether (2.18 ml, 27.5 mmol), triphenylphosphine (3.57g, 13.2 mmol), diisopropyl azodicarboxylate (2.31 ml, 13.2 mmol). The crude product can be purified by flash chromatography (eluent: methanol/di¬ chloromethane 1 :9): yellow syrup, TLC: R_f=0.33 (methanol/dichloromethane 1 :9), HPLC: t_R=10.56 min.

Example 14: f(2-[(1 -Acetoxy-2-methylpropoxycarbonylmethylW2-hvdroxybenzyl)aminol- ethyl)-(2-hvdroxybenzyhaminolacetic acid

Preparation analogously to Example 11 , mixture: [{2-[(1 -acetoxy-2-methylpropoxycarbonyl- methyl)-(2-methoxymethoxybenzyl)amino]ethyl}-(2-methoxymethoxybenzyl)amino]acetic acid (2.6 g, 4.4 mmol). The residue obtained after working up does not crystallize and is therefore purified by flash chromatography (eluent: methanol/dichloromethane/water/glacial acetic acid 10:90:1 :0.5) and recrystallization from ethyl acetate/ether. The title compound is obtained as a colourless powder: m.p. 118-122 °C TLC: R» = 0.25 (methanol/ dichloro- methane/water/glacial acetic acid 10:90:1:0,5), HPLC: t_R = 11.61 mm.

a) [(2-fπ-Acetoxy-2-methylpropoxycarbonylmethyl)-f2-methoxymethoxybenzyl)amιnolethyll- (2-rnθthoxymethoxybenzvDamιnolacθtic acid: 1 -Chloro-2-methylpropyl acetate (M. Neuen- schwander, R. Iseh, Helv. Chim. Acta 60, 1061 (1977), [13398-05-5], 7.53g, 50 mmol) is added in one portion to a solution of disodium [{2-[ethoxycarbonylmethyl-(2-methoxymeth- oxybenzyl)amιno]ethyl}-(2-methoxymethoxybenzyl)amιno]acetate (Example 11b, 11.57 g, 20 mmol) in N,N-dιmethylformamιde. The clear orange-red-coioured solution is heated at 100 °C for 2 hours. After a short time, a fine pale yellow-coloured precipitate is formed. To complete the reaction, the suspension is stirred at 60 °C for 8 hours and at room tempera¬ ture overnight. The solvent is then removed in a high vacuum. The residual dark brown- coloured syrup is taken up in ethyl acetate, extracted by shaking (1x sat sodium hydrogen- carbonate solution, 3x water, 1x brine), dried over magnesium sulfate, filtered and evapo¬ rated. The residual dark red-coloured syrup is purified further by flash chromatography (eluent: methanol/dichloromethane/glaαal acetic acid 10:90:1) The title compound can be isolated as a pale yellow syrup:TLC: R, = 0.31 (methanol/dichloromethane/water/glacial acetic acid 10 90 1 :0.5), HPLC: t_R = 12.50 mm.

Example 15' ((2-Hvdroxybenzyl)-(2-f(2-hvdroxybenzvπmethylcarbamoylmethylamιnolethyl>- amιno)acetιc acid, trifluoroacetic acid salt

Preparation Method A: A solution of ((2-hydroxybenzyl)-{2-[(2-hydroxybenzyl)ethoxy- carbonylmethylamιno]ethyl}amιno)acetιc acid (Example 3, modification B, 2.5 g, 6 mmol) in 40% methylamine in water (20 ml) is stirred at 50°C in a glass autoclave for- 24 hours. After cooling, the solution is evaporated to dryness on a rotary evaporator. The residue is taken up in ethanol (10 ml) and the solution is carefully adjusted to about pH 6 by addition of 1 M hydrochloric acid. The mixture is evaporated again and the residue is purified by medium pressure chromatography (stationary phase: Merck Lichroprep RP-18, 15-25 μm, Art. No. 13901 , eluent: acetonitnle/water + 0.1% trifluoroacetic acid). After evaporation of the eluate and lyophilization (water/dioxane 1 :9, 8 ml), the product is obtained in the form of a pale pink-coloured, amorphous, hygroscopic powder: TLC: Rp0.40 (methanol/dichloromethane/ glacial acetic acid 20:80:0.5), HPLC: t_R = 8.08 mm. Preoaration Method B: Concentrated hydrochloric acid (5 ml) is carefully added dropwise to an ice-cooled solution of ((2-methoxymethoxybenzyl)-{2-[(2-methoxymethoxybenzyl)-methyl- carbamoylmethylamino]ethyl}amino)acetic acid (2.45g, 5 mmol) in ethanol (50 ml). The so¬ lution immediately turns deep red. After completion of the addition, the ice bath is removed and the mixture is additionally stirred at room temperature for a further 6 hours. The solution is then evaporated at room temperature in a high vacuum. The residue is taken up in di¬ chloromethane, treated with water and brought to pH 4 by addition of saturated sodium hy- drogencarbonate solution. The organic phase is separated off and the aqueous phase is extracted twice with dichloro-methane. The combined extracts are washed (1x buffer pH 4, 1x brine), dried (sodium sulfate), filtered and evaporated. The crude product is purified as described in Preparation Method A.

a) [(2-fMethoxycarbonylmethyl-(2-methoxymethoxybenzyl)amιno]ethyl)-(2-methoxymethoxy- benzylteminolacetic acid: Finely powdered anhydrous potassium carbonate is added in one portion to a solution of disodium [(2-[ethoxycarbonylmethyl-(2-methoxymethoxybenzyl)- amιno]ethyl}-(2-methoxymethoxybenzyl)amino]acetate (Example 14b, 52.0g, 90 mmol) in N,N-dιmethylformamide (300 ml). The suspension is vigorously stirred for 15 minutes, then methyl iodide (14 ml, 225 mmol) is slowly added dropwise. In a slightly exothermic reaction, the colour of the mixture changes from deep red to orange. The mixture is stirred overnight at room temperature. The suspension is then filtered and the filtrate is concentrated in a high vacuum. The residue, solidifying to a waxy mass, is treated with ethyl acetate (600 ml) and water. The organic phase is separated off, washed (1x sat. sodium hydrogencarbonate solution, 4x water, 1x brine), dried over magnesium sulfate and evaporated. The residual orange viscous syrup is purified further by flash chromatography (eluent: methanol/dichloro- methane/glacial acetic acid 5:95:1 ) and drying in a high vacuum at 50 °C: orange resin, TLC: R_f=0.35 (methanol/dichloromethane/water/glaciat acetic acid 90:10:1 :0.5), HPLC: t_R = 11.54 min.

b) ((2-Methoxymethoxybenzyl)-?2-f(2-methoxymethoxybenzyl)methylcarbamoylmethyl- amino}ethyl}amino)acetic acid: f(2-fmethoxvcarbonylmethyl-(2-methoxymethoxybenzyl)- amino]ethyl}-(2-methoxymethoxybenzyl)amino]acetic acid (2.45 g, 5 mmol) is dissolved in a 33 % methylamine solution in ethanol (25 ml) and the solution is stirred overnight at room temperature. The mixture is then evaporated in a high vacuum. The residual viscous dark- brown syrup is dissolved in ethyl acetate, and the solution is washed (2x buffer pH 4, 1x water, 1x brine), dried over magnesium sulfate, filtered and evaporated. The title compound remains in the form of a yellow-orange-coloured syrup, which can be further processed without further treatment: TLC: R_f=0.39 (methanol/dichloromethane/water/glacial acetic acid 90:10:1 :0.5), HPLC: t_R = 9.12 mm.

Example 16: r(2-fDιmethylcarbamoylmethyl-(2-hvdroxybenzyπamιnolethyll-(2-hvdroxy- benzvhaminolacetic acid, trifluoroacetic acid salt

Preparation Method A: Analogously to Example 15, mixture: ((2-hydroxybenzyl)- {2-[(2-hydroxybenzyl)ethoxycarbonylmethylammo]ethyl}amιno)acetιc acid (Example 3, modification B, 1 g, 2.4 mmol), dimethylamine 40 % in water (25 ml). The crude product was purified by medium pressure chromatography and lyophihzation (conditions: see Example 18): pale pink, amorphous, hygroscopic very voluminous powder, TLC: R_f=0.55 (methanol/ dichloromethane/glacial acetic acid 20:80:0.5), HPLC: t_R = 8.30 mm.

Preparation Method B: Analogously to Example 15, mixture: [{2-[dιmethylcarbamoyl-methyl- (2-methoxymethoxybenzyl)amιno]ethyl}-(2-methoxymethoxybenzyl)amιno]acetιc acιd (2 57 g, 5 mmol), ethanol (50 ml), concentrated hydrochloric acid (5 ml). The crude product is purified as described in Preparation Method A.

a) r(2-[Dιmethylcarbamoylmethyl-(2-methoxymethoxybenzyl)amιno1ethyll-(2-methoxymeth- oxybenzvPaminolacetic acid: Gaseous dimethylamine is passed into an ice-cooled solution of [{2-[methoxycarbonylmethyl-(2-methoxymethoxybenzyl)amιno]ethyl}-(2-methoxymethoxy- benzyl)amιno]acetιc acid (Example 15a, Preparation Method B, 2 45g, 5 mmol) in tetrahy¬ drofuran (50 ml) until 4.5 g (100 mmol) have been absorbed. The mixture is then stirred overnight at room temperature The clear orange-red solution obtained is evaporated. A dark brown-coloured syrup remains The crude product is taken up in ethyl acetate, washed (2x buffer pH 4, 1x water, 1x brine), dried over magnesium sulfate and evaporated. An or¬ ange syrup remains, which can be further processed without further purification TLC: R,=0 19 (methanol/dichloromethane 1 :19), HPLC: t_R = 11.27 mm

Example 17: r(2-HvdroxybenzylH2-((2-hydroxybenzylH(2-methoxyethylcarbamovhmethyl1- aminolethvOaminolacetic acid hemihvdrate

Preparation Method A: A solution of ((2-hydroxybenzyl)-{2-[(2-hydroxybenzyl)ethoxy- carbonylmethylamιno]ethyl}amιno)acetιc acid (Example 3, modification B, 2.5 g, 6 mmol) in 2-methoxyethylamιne (25 ml) is stirred overnight at 50 °C with excluston of air and moisture. The solvent is then removed in a high vacuum and the residue is taken up in water. The solution obtained is adjusted to pH 5 by addition of 1 M hydrochloric acid and evaporated again. The beige-coloured foamy residue is purified by flash chromatography (stationary phase: silica gel RP-18, 40-63 μm, eluent: water → acetonitrile/water 1 :9 → acetonitrile/ water 1 :4). Lyophilization from water (10 ml) gives the title compound in the form of a volu¬ minous pale pink-coloured powder: TLC: R_f=0.60 (methanol/dichloromethane/glacial acetic acid 20:80:0.5)19), R_f=0.76 (RP-18, acetonitrile/water 1 :1), HPLC: t_R = 8.17 min.

Preparation Method B: A 4 M hydrogen chloride solution in ether (5 ml, 20 mmol) is slowly added dropwise to an ice-cooled solution of [{2-[[(2-methoxyethylcarbamoyl)methyl]- (2-methoxymethoxybenzyl)amino]ethyl}-(2-methoxymethoxybenzyl)amino]acetic acid (2.13 g, 4 mmol) in a mixture of tetrahydrofuran (40 ml) and isopropanol (10 ml). The colour immediately changes from orange-yellow to deep red. The ice bath is removed and the mixture is stirred at room temperature overnight. The solvent is then removed under re¬ duced pressure. The residual dark brown resin is dissolved in dichloromethane, extracted by shaking (1 x sat. sodium hydrogencarbonate solution, 2x buffer pH 4, 1x brine), dried over sodium sulfate and evaporated. The crude product remaining as an orange-coloured syrup is further purified as described in Preparation Method A.

a) (2-[f(2-Methoxyethylcarbamovπmethyll-(2-methoxymethoxybenzyl)aminolethyl)- (2-methoxymethoxybenzyl)amino1acetic acid: A solution of [{2-[methoxycarbonylmethyl- (2-methoxymethoxybenzyl)amino3ethyl}-(2-methoxymethoxybenzyl)amino]acetic acid (Example 15a, Preparation Method B, 2.45g, 5 mmol) in 2-methoxymethylamine (25 ml) is stirred at room temperature overnight. The now clear red-brown-coloured mixture is then evaporated in a high vacuum. The residue is taken up in ethyl acetate, washed (2x buffer pH 4, 1x water, 1x brine), dried over magnesium sulfate and evaporated. The title com¬ pound obtained as a reddish syrup can be further processed without further purification: TLC: R_f=0.36 (methanol/dichloromethane/glacial acetic acid 20:80:0.5), HPLC: t_R = 9.68.

Example 18: f(2-rEthoxycarbonylmethyl-(5-fluoro-2-hvdroxybenzyl)amino1ethylH5-fluoro- 2-hvdroxybenzyl)aminolacetic acid

A suspension of ethyl [{2-[ethoxycarbonylmethyl-(5-fluoro-2-hydroxybenzyl)amino]ethyl}- (5-fluoro-2-hydroxybenzyl)amino]acetate (5 g, 10.4 mmol) in ethanol (100 ml) is treated in one portion with 2 M sodium hydroxide solution (5.2 ml, 10.4 mmol) and stirred overnight at an internal temperature of 40 ^CC The resulting colourless fine suspension is cooled in an ice bath and filtered, and the solid is washed with cold ethanol and sucked dry. The crude product is taken up again in ethanol (100 ml) and treated with glacial acetic acid (4 ml). Af¬ ter 2 hours, everything has gone into solution. The resin which remains after evaporation of the solution is purified further by flash chromatography (eluent: methanol/dichloromethane/ glacial acetic acid 10:90:0.5) and recrystallization from ethanol/methyl terf-butyl ether. Pale pink crystals, m.p. 104-108 °C, TLC: R_f=0.40 (dichloromethane/methanol/glacial acetic acid 90 10:0.5), HPLC: t_R=9.93 mm.

a) N.N'-Bιs(5-fluoro-2-hvdroxybenzylιdene)ethylenedιamιne: A solution of crude 5-fluoro- 2-hydroxybenzaldehyde (63.9 g, 228 mmol; [347-54-6] still contains about 50 % p-fluoro- phenol, R. Aldred, R. Johnston, D. Levin, J. Neilan; J. Chem. Soc. Perkm Trans I, 1823 (1994)) is slowly added dropwise to a solution of ethylenediamine (7.62 ml, 1 14 mmol) tn methanol (140 ml). With slight warming, the product begins to precipitate in the form of yel¬ low crystals The suspension is stirred further at room temperature overnight and then cooled in an ice bath The precipitated crystals are filtered off on a suction filter, washed with cold methyl terf-butyl ether, sucked dry and dried in a high vacuum. Yellow crystals. HPLC. t_R=10.61 mm.

b) N.N'-Bιs(5-fluoro-2-hvdroxybenzyl)ethylenedιamιne A solution of N,N'-bιs(5-fluoro- 2-hydroxybenzylιdene)ethylenedιamιne (41.5 g, 136 mmol) in tetrahydrofuran (370 ml) is treated with platinum dioxide (900 mg) and shaken at normal pressure and room tempera¬ ture under a hydrogen atmosphere After the calculated amount of hydrogen has been ab¬ sorbed, the reaction is stopped The catalyst is filtered off. Evaporation of the filtrate yields the product in the form of yellow crystals: m.p 111 -116 °C, TLC: R_f = 0.37 (methanol/dichloromethane/water/glacial acetic acid 27:75:5:0.5), HPLC- t_R= 6 88 mm.

c) [(2-fCarboxymethyl-(5-fluoro-2-hydroxybenzvπamιnolethyl)-(5-fluoro-2-hvdroxybenzvh- ammolacetic acid hydrochloride: (Dexter, M ; Pnnciotto, J.V.; Rubin, M; FR 1 355 147, J.R. Geigy AG, 23.3.1994, CA 61 4882a (1964)) A suspension of N,N'-bιs(5-fluoro-2-hydroxy- benzyl)ethylenedιamιne (20 g, 64.9 mmol) in a solution of sodium hydroxide (2.6 g,

65 mmol) in water (90 ml) is slowly treated with a solution of bromoacetic acid (18 g, 130 mmol) in water (160 ml) containing sodium hydrogencarbonate (10.9 g, 130 mmol). The mixture obtained is warmed to 40 °C and kept at pH 12 by continuous dropwise addition of 30 % sodium hydroxide solution. After the calculated amount of sodium hydroxide solution has been consumed, the reaction is stopped and the mixture is cooled to room temperature. By addition of 6 M hydrochloric acid, the now dark-coloured solution is adjusted to pH 2. After some time, the product begins to precipitate as a fine beige powder. The crystals are filtered off, washed with ice water, sucked dry and dried in a high vacuum. Beige powder, m.p. 133-137 ^CC (dec), TLC: 0.34 methanol/dichloromethane/water/glacial acetic acid 27:75:5:0.5), HPLC: t_R = 8.58 min.

d^ Ethyl rf2-rEthoxycarbonylmethyl-(5-fluoro-2-hvdroxybenzyllamino1ethyll-(5-fluoro-2- hvdroxy-benzvDaminoacetate: A moderate stream of hydrogen chloride is passed with ice cooling for 20 minutes into a suspension of [{2-[carboxymethyl-(5-fluoro-2-hydroxy-benzyl)- ammo]ethyl}-(5-fluoro-2-hydroxybenzyl)amιno]acetιc acid hydrochloride (23.7 g, 55.8 mmol) in ethanol (400 ml). The mixture is then warmed to 50 °C for 18 hours. After cooling, the mixture is evaporated and the oily partially crystalline residue is treated with dichloro¬ methane (250 ml) and saturated sodium hydrogencarbonate solution (250 ml). The dichloro¬ methane phase is separated off, washed (1x water, 1 x brine), dried over sodium sulfate, filtered and evaporated. Recrystallization of the residue from hot ethanol yields the title compound in the form of colourless flakes, m.p. 107-109 °C, TLC: R_f=0.66 (ethyl acetate/ hexane 1 :1), HPLC: t_R= 11.05 mm.

Example 19: Sodium ((5-bromo-2-hvdroxybenzylH2-f(5-bromo-2-hvdroxybenzyl)ethoxy- carbonylmethylamιno1ethyl)amιno)acetate:

Preparation analogously to Example 18, mixture: ethyl [{2-[ethoxycarbonylmethyl-(5-bromo- 2-hydroxybenzyl)amιno]ethyl}-(5-bromo-2-hydroxybenzyl)amιno]acetate (2.56 g, 4.25 mmol), ethanol (50 ml), 2 M sodium hydroxide solution (2.1 ml, 4.2 mmol). The pre¬ cipitated sodium salt is filtered off on a suction filter, washed with ice-cold methanol, sucked dry and dried at 60 °C in a high vacuum. Colourless powder: m.p. 223-224 °C (dec), TLC: R,=0.12 (methanol/dichloromethane 1 :9), HPLC: t_R=10.88 mm.

a) N,N'-Bιs(5-bromo-2-hvdroxybenzylidene)ethylenedιamιne: (M.R. Bermejo, M. Fondo, A. Garcia-Deibe, M. Rey, J. Sanmartin, A. Sousa, M. Watkinson, CA. McAuliffe, R.G. Prit- chard, Polyhedron 1j>, 4185 (1996)) Preparation analogously to Example 18a, mixture 125 mmol: ethylenediamine (8.36 g, 125 mmol), 5-bromo-2-hydroxybenzaldehyde (50.26 g, 250 mmol), methanol (500 ml). Bright yellow-coloured crystals: m.p. 191-193 °C, TLC: R_f=013 (ethyl acetate/hexane 1 :4), HPLC: t_R=12.21 min.

b) N,N'-Bis(5-bromo-2-hvdroxybenzvπethylenediamιne: (E. Wong, S. Liu, S. Rettig, C Or- vig, Inorg. Chem. 34, 3057 (1995)) Sodium borohydride (4.76 g, 126 mmol) is added in por¬ tions in the course of 1 hour to a vigorously stirred suspension of N,N'-bis(5-bromo-2- hydroxy-benzylidene)ethylenediamine (25.57 g, 60 mmol) in ethanol (350 ml). After comple¬ tion of the addition, the now colourless slightly cloudy solution is stirred overnight at room temperature. During this time, the product precipitates in the form of colourless crystals. The crystals are filtered off with suction, washed with cold ethanol, sucked dry and dried in a high vacuum. Colourless crystals: m.p. 175-176 °C, TLC: R₍=0.19 (2% methanol in di¬ chloromethane), HPLC: t_R=8.44 min.

c⁾ [{2-fCarboxymethyl-(5-bromo-2-hvdroxybenzvπamino1ethyl>-(5-bromo-2-hvdroxybenzyl)- aminolacetic acid: (J. G. Wilson, Aust. J. Chem. 4J,, 173 (1988), Preparation analogously to: J.-P. Gaiey, J. Dumats, FR 2 698 095, L'Oreal, 13.11.1992) Preparation analogously to Ex¬ ample 18c, mixture: N,N'-bis(5-bromo-2-hydroxybenzyl)ethylenediamine (17.2 g, 40 mmol), bromoacetic acid (11.1 g, 80 mmol). The product already crystallizes on acidifying to pH 5. The precipitated material is filtered off with suction, washed with cold methanol, sucked dry and dried in a high vacuum: pale pink crystals: m.p. 205-206 °C, TLC: R,=0.52 (methanol/ dichioromethane/water/glacial acetic acid 27:75:5:0.5), HPLC: t_R=12.21 min.

d) Ethyl f(2-fEthoxycarbonylmethyl-f5-bromo-2-hvdroxybenzyl)aminolethyl)-(5-bromo- 2-hydroxy-benzyl)aminolacetate: Preparation analogously to Example 18d, mixture: [{2-[carboxymethyl-(5-bromo-2-hydroxybenzyl)amino]ethyl}-(5-bromo-2-hydroxybenzyl)- aminojacetate (12.5 g, 23 mmol), ethanol (250 ml). Recrystallization of the crude product from ethanol yields a colourless finely crystalline powder: m.p. 135-137 ^CC, TLC: R,=0.46 (ethylacetate/hexane 1 :2), HPLC: t_R=12.14 min.

Example 20: Sodium [(2-fethoxycarbonylmethyl-(2-hydroxy-5-methoxybenzyl)amino1ethyl)- (2-hvdroxy-5-methoxybenzyl)amino1acetate

Preparation analogously to Example 19, mixture: [{2-[ethoxycarbonylmethyl-(2-hydroxy- 5-methoxybenzyl)amino]ethyl}-(2-hydroxy-5-methoxybenzyl)amino]acetate (5.05 g, 10 mmol), 2 M sodium hydroxide solution (10 mmol), ethanol (100 ml). Almost colourless amorphous powder: m.p. 187-188 °C, TLC: R, = 0.26 (methanol/dichloromethane/water/ glacial acetic acid 10:90:1 :0.5), HPLC: t_R=9.15.

a) N.N'-Bis(2-hvdroxy-5-methoxybenzylidene)ethylenediamine: (A. Nishinaga, T. Tsutsu, H. Moriyama, T. Wazaki, T. Mashino, Y. Fujii, J. Mol. Catal., 83, 117 (1993)) Preparation analogously to Example 18a, mixture: 2-hydroxy-5-methoxybenzaldehyde (45.7 g, 300 mmol), ethylenediamine (10 ml, 150 mmol), methanol (500 ml). Yellow flakes: m.p. 163- 164 °C, TLC: R_f=0.55 (ethyl acetate/hexane 1 :1 ), HPLC: t_R=10.75 mm.

b) N.N'-Bιs(2-hvdroxy-5-methoxybenzyl)ethylenedιamine: Preparation analogously to Ex¬ ample 18b, mixture: N,N'-bιs(2-hydroxy-5-methoxybenzylιdene)ethylenedιamιne (32.8 g, 100 mmol), platinum dioxide (650 mg), tetrahydrofuran (500 ml). Recrystallization from hot acetonitrile yields colourless crystals: m.p. 153-154 °C, TLC: R_f=0.16 (ethyl acetate/hexane 1 :1 ), HPLC: t_R=6.70 mm.

c) [{2-[Carboxymethyl-(2-hvdroxy-5-methoxybenzvhamιno1ethyll-(2-hvdroxy-5-methoxy- benzvDaminolacetic acid, hydrobromide: (Preparation analogously to: J.-P. Galey, J. Du- mats, FR 2 698 095, L'Oreal, 13.11.1992) Preparation analogously to Example 18c, mix¬ ture: N,N'-bis(2-hydroxy-5-methoxybenzyl)ethylenediarnine (16.6 g, 50 mmol), bromoacetic acid (13.9 g, 100 mmol). The title compound is crystallized by acidifying to pH 2 with con¬ centrated hydrobromic acid. Almost colourless crystals: m.p. 145-147 ^CC (dec), TLC: R,=0.46 (methanol/dichloromethane/water/glacial acetic acid 27:75:5:0.5), HPLC: t_R=7.89 mm.

d) Ethyl f(2-[ethoxycarbonylmethyl-(2-hvdroxy-5-methoxybenzyl)amιnolethyl)-(2-hvdroxy- 5-methoxybenzyl)amιno]acetate: Preparation analogously to Example 18d, mixture: [{2-[carboxymethyl-(2-hydroxy-5-methoxybenzyl)amιno]ethyl}-(2-hydroxy-5-methoxybenzyl)- amιno]acetιc acid, hydrobromide (11.2 g, 22 mmol), ethanol (350 ml). Recrystallization from methyl terf-butyl ether/hexane yields fine colourless crystals: m.p. 75-76 °C, TLC. R_f=0.29 (ethyl acetate/hexane 1 :2), HPLC: t_R=11.05 mm.

Example 21 : frans-ff2-fEthoxycarbonylmethyl-(2-hvdroxybenzyl)amιno1cvclohexyl)- (2-hvdroxybenzyl)amιno)acetιc acid

Preparation analogously to Example 18, mιxture:ethyl frans-[{2-[ethoxycarbonyl-(2-hydroxy- benzyl)amιno]cyclohexyl}-(2-hydroxybenzyl)amino]acetate (9.4 g, 18.9 mmol), 2 M sodium hydroxide solution (9.4 ml, 18.8 mmol), ethanol (150 ml). The product obtained after chro- matographic purification can be crystallized by taking it up in ethanol: colourless powder, m.p. 189-191 °C, TLC: R_f=0.33 (methanol/dichloromethane 1 :9), HPLC: t_R=10.22 mm.

a) rrans-N,N'-Bis-(2-methoxymethoxybenzyltdene)cvclohexane-1.2-diamine: Preparation analogously to Example 18a, mixture: trans-1 , 2-dιamιnocyclohexane (23.5 ml, 196 mmol), 2-methoxymethoxybenzaldehyde (65 g, 391 mmol, [5533-04-0], H.F. Campbell et al., J Med. Chem. 1992, 35, 895), methanol (130 ml). As the product does not crystallize, the sol¬ vent is removed in vacuo and the brownish oily residue is crystallized by treatment with hexane. Almost colourless crystals: m.p. 90-93 °C , TLC: R_f=0.41 (ethyl acetate/hexane 1 -4), HPLC: t_R=11.05 min.

b) frans-N, N'-Bιs-(2-methoxymethoxybenzyl)cvclohexane-1.2-dιamιne: Preparation analo¬ gously to Example 18b, mixture: frans-N, N'-Bιs-(2-methoxymethoxybenzylιdene)-cyclo- hexane-1 ,2-dιamιne (82.5 g, 200 mmol), platinum dioxide (1.5 g), tetrahydrofuran (1.6 I) Dark yellow syrup: TLC: R_f=0.71 (methanol/dichloromethane/water/glacial acetic acid 27:75:5:0.5), HPLC: t_R=9.47 mm.

c) Ethyl f/-ans-r(2-fethoxycarbonylmethyl-(2-methoxymethoxybenzvπamιno1cvclohexyl)- (2-meth-oxymethoxybenzyl)amιno]acetate: A solution of ethyl todoacetate (7.1 ml, 51 mmol) in dichloromethane (10 ml) is added dropwise with ice-cooling to a solution of frans-N, N'-bis- (2-methoxymethoxybenzyl)cyclohexane-1 ,2-dιamιne (10 g, 24.1 mmol) and tπethylamine

(6 ml, 50.7 mmol) in dichloromethane (35 ml) such that the internal temperature does not exceed 10 °C The mixture is stirred further at room temperature overnight. The reaction solution is then diluted with dichloromethane (250 ml), washed (2x water, 1 x brine), dried over sodium sulfate, filtered and evaporated. The residual dark yellow syrup is processed further in the next step without further purification: HPLC: t_R=13.53 mm

d) Ethyl frans-f(2-fethoxycarbonyl-(2-hvdroxybenzyl)amιnolcvclohexyl)-(2-hvdroxybenzyl)- ammolacetate A moderate stream of hydrogen chloride is passed with ice-coolmg (max. internal temperature 25°C) for 10 minutes into a solution of ethyl frans-[{2-[ethoxycarbonyl- methyl-(2-methoxymethoxybenzyl)amιno]cyclohexyl}-(2-methoxymethoxybenzyl)amιno]- acetate (44.6 g, 76 mmol) in ethanol (500 ml). To complete the reaction, the mixture is stirred further at room temperature overnight The solvent is then removed in vacuo and the resinous residue is treated with ethyl acetate (250 ml) and saturated sodium hydrogencar¬ bonate solution (250 ml). The organic phase is separated off, washed (1x water, 1x brine), dried over sodium sulfate and evaporated. The residual foamy crude product is purified by flash chromatography (eluenf ethyl acetate/hexane 1 4) and recrystallization from diisopro¬ pyl ether/hexane. Colourless crystals: m.p. 100-103°C, TLC. R_f=0.32 (ethyl acetate/hexane 1 :4), HPLC: t_R=12.14 mιn Examples A to D: Pharmaceutical preparations

The expression "active ingredient" is below understood as meaning a compound of the for¬ mula I, in free form or in the form of a pharmaceutically acceptable salt, in particular a com¬ pound of the type which is described as a product in one of the above examples.

Example A: Tablets, comprising 200 mg of active ingredients each, can be prepared as fol¬ lows:

Composition (10.000 tablets ϊ

Active ingredient 2000.0 g

Lactose 500.0 g

Potato starch 352.0 g

Gelatin 8.0 g

Talc 60.0 g

Magnesium stearate 10.0 g

Silica (highly disperse) 20.0 g

Ethanol q.s.

The active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve. After drying, the remainder of the potato starch, the magnesium stearate, the talc and the silica is admixed and the mixture is compressed to give tablets of weight 295.0 mg each and 200 mg active ingredient content, which, if desired, can be provided with breaking notches for finer adjustment of the dosage.

Example B: Coated tablets, each comprising 400 mg of active compound, can be prepared as follows.

Composition (1.000 Tablets)

Active ingredient 400.0 g

Lactose 100.0 g

Maize starch 70.0 g

Talc 8.5 g

Calcium stearate 1.5 g

Hydroxypropylmethylcellulose 2.36 g

Shellac 0.64 g

Water q.s.

Dichloromethane q.s.

The active ingredient, the lactose and 40 g of the maize starch are mixed and moistened and granulated with a paste prepared from 15 g of maize starch and water (with warming). The granules are dried, and the remainder of the maize starch, the talc and the calcium stearate is added and mixed with the granules. The mixture is compressed to give tablets and these are coated with a solution of hydroxypropylmethylcellulose and shellac in di¬ chloromethane; final weight of the coated tablet: 583 mg.

Example C: Hard gelatin capsules, comprising 500 mg of active ingredients, can be pre¬ pared, for example, in the following manner:

Composition (for 1 ,000 capsules):

Active ingredient 500.0 g

Lactose 250.0 g

Microcrystalline cellulose 30.0 g

Sodium lauryl sulfate 2.0 g

Magnesium stearate 8.0 g The sodium lauryl sulfate is sieved into the lyophilized active ingredient through a sieve having a mesh width of 0.2 mm. Both components are intimately mixed. Then the lactose is first sieved in through a sieve having a mesh width of 0.6 mm and the microcrystalline cel¬ lulose is then sieved in through a sieve having a mesh width of 0.9 mm. After that, the in¬ gredients are again intimately mixed for 10 minutes. Finally, the magnesium stearate is sieved in through a sieve having a mesh width of 0.8 mm. After 3 minutes' further mixing, 790 mg each of the formulation obtained are dispensed into hard gelatin capsules of suit¬ able size.

Example D: Oral suspension powder, comprising 300 mg of active ingredient, can be pre¬ pared as follows

Composition (1 administration):

Active ingredient 300 mg

Hydroxypropylcellulose (Klucel HF) 50 mg

Tartaric acid 100 mg

Sodium lauryl sulfate 100 mg

The sodium lauryl sulfate is sieved into the lyophilized active ingredient through a sieve having a mesh width of 0.2 mm. Both components are intimately mixed. Then the mi¬ crocrystalline cellulose is sieved in through a sieve having a mesh width of 0.9 mm. After this, the ingredients are again intimately mixed for 10 minutes. Finally, the tartaric acid is sieved in through a sieve having a mesh width of 0.8 mm. After 3 minutes' further mixing, the mixture is dispensed into a container having a capacity of at least 10 ml. For use, the mixture is made up to 10 ml with water and vigorously shaken.

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula I

in which

R is hydrogen or acyl;

R² is OR³ or NR⁴R⁵;

R³ is unsubstituted or substituted lower alkyl, cyclo-lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or lower alkoxycarboxy-lower alkyl;

R⁴ and R⁵ independently of one another are hydrogen or unsubstituted or substituted lower alkyl;

R⁶ and R⁷ independently of one another are hydrogen, halogen, lower alkyl or lower alkoxy;

R⁸ and R⁹ individually are hydrogen or together are n-butylene; and salts thereof.

2. A compound according to claim 1 , wherein

R¹ is hydrogen;

R² is OR³ or NR⁴R^S;

R³ is unsubstituted or substituted lower alkyl, cyclo-lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or lower alkoxycarboxy-lower alkyl;

R⁴ and R⁵ independently of one another are hydrogen or unsubstituted or substituted lower alkyl;

R⁶ and R⁷ are hydrogen;

R⁸ and R⁹ individually are hydrogen or together are n-butylene; and salts thereof.

3. A compound according to claim 1 , wherein R¹ is hydrogen;

R² is OR³;

R³ is unsubstituted or substituted lower alkyl, cyclo-lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or lower alkoxycarboxy-lower alkyl;

R⁶ and R⁷ are hydrogen;

R⁸ and R⁹ are hydrogen; and pharmaceutically acceptable salts thereof.

4. A compound according to claim 1 , wherein R¹ is hydrogen;

R² is OR³;

R³ is unsubstituted or substituted lower alkyl, cyclo-lower alkyl, lower alkoxy-lower alkyl or lower alkoxycarbonyl-lower alkyl;

R⁶ and R⁷ are hydrogen;

R⁸ and R⁹ are hydrogen; and pharmaceutically acceptable salts thereof.

5. A compound according to claim 1 selected from the group consisting of ((2-hydroxybenzyl)-{2-[(2-hydroxybenzyl)methoxycarbonylmethylamino]ethyl}amino)acetic acid,

((2-hydroxybenzyl)-{2-[(2-hydroxybenzyl)ethoxycarbonylmethylamino]ethyl)amino)acetic acid,

[(2-[(1-acetoxy-2-methylpropoxycarbonylmethyl)-(2-hydroxybenzyl)amino]ethyl}- (2-hydroxybenzyl)amino]acetic acid, and pharmaceutically acceptable salts thereof.

6. A pharmaceutical preparation comprising a compound according to any one of claims 1 to 5 and at least one pharmaceutically acceptable carrier.

7. A compound according to any one of claims 1 to 5 for use in a method for the therapeutic treatment of the animal or human body.

8. A compound according to any one of claims 1 to 5 for use in the treatment of illnesses which cause an excess of iron in the human or animal body or are caused by it.

9. The use of a compound according to any one of claims 1 to 5 for the production of phar¬ maceutical preparations.

10. The use of a compound according to any one of claims 1 to 5 for the production of pharmaceutical preparations for the treatment of an excess of iron in the human or animal body.

1 1. A process for the preparation of a compound of the formula I according to claim 1 , and salts thereof, which comprises

a) hydrolysmg a compound of the formula II

in which R\ R², R⁶, R⁷, R^β and R⁹ are as defined under formula I and X is a leaving group, or

b) reacting a compound of the formula III

in which R\ R⁶, R⁷, R^β, R⁹ and X are as defined under formula II, with a compound of the formula Ilia

R²-H <"^la) in which R² is as defined under formula I, or

c) reacting a compound of the formula IV

in which R , R , R , R and R are as defined under formula I, with a compound of the for¬ mula IVa

R³— Y (IVa)

in which R³ is as defined under formula I and Y is halogen, it being possible, if appropriate, for substituents in protected form to be present, and then converting this compound, if necessary, into a compound of the formula I by removal of protective groups, and, if desired, converting a compound of the formula I into another compound of the formula I, and/or, if desired, converting a salt obtained into the free com¬ pound or into another salt, and/or, if desired, converting a free compound of the formula I obtained having salt-forming properties into a salt.